Environmental stressors and cardiovascular risk: Impact of environmental noise exposure on vascular oxidative stress and damage

Epidemiological studies have demonstrated that traffic noise exposure is associated with cardiovascular diseases such as arterial hypertension, myocardial infarction and stroke. Persistent chronic noise exposure increases the risk of cardiovascular and metabolic diseases such as arterial hypertension, coronary artery disease, diabetes and stroke. Large epidemiological studies (reviewed in Munzel et al. Eur. Heart J. 2017, 38 (8):550–556) point towards a link between the incidence of ischemic heart diseases and exposure to noise, supporting its role as an independent cardiovascular risk factor. Recently, the underlying molecular mechanisms leading to noise-dependent adverse effects on the va…

Redox regulation of genome stability by effects on gene expression, epigenetic pathways and DNA damage/repair

Reactive oxygen and nitrogen species (e.g. H2O2, nitric oxide) confer redox regulation of essential cellular signaling pathways such as cell differentiation, proliferation, migration and apoptosis. In addition, classical regulation of gene expression or activity, including gene transcription to RNA followed by translation to the protein level, by transcription factors (e.g. NF-κB, HIF-1α) and mRNA binding proteins (e.g. GAPDH, HuR) is subject to redox regulation. This review will give an update of recent discoveries in this field, and specifically highlight the impact of reactive oxygen and nitrogen species on DNA repair systems that contribute to genomic stability. Emphasis will be placed …

The impact of aircraft noise on vascular and cardiac function in relation to noise event number: a randomized trial

Abstract Aims Nighttime aircraft noise exposure has been associated with increased risk of hypertension and myocardial infarction, mechanistically linked to sleep disturbance, stress, and endothelial dysfunction. It is unclear, whether the most widely used metric to determine noise exposure, equivalent continuous sound level (Leq), is an adequate indicator of the cardiovascular impact induced by different noise patterns. Methods and results In a randomized crossover study, we exposed 70 individuals with established cardiovascular disease or increased cardiovascular risk to two aircraft noise scenarios and one control scenario. Polygraphic recordings, echocardiography, and flow-mediated dila…

Disturbed Lipid Metabolism in Diabetic Patients with Manifest Coronary Artery Disease Is Associated with Enhanced Inflammation

Background: Diabetic vasculopathy plays an important role in the pathophysiology of coronary artery disease (CAD) with oxidative stress as a strong mediator. This study aims to elucidate the underlying pathomechanisms of diabetic cardiac vasculopathy leading to coronary disease with an emphasis on the role of oxidative stress. Therefore, novel insights into antioxidant pathways might contribute to new strategies in the treatment and prevention of diabetic CAD. Methods: In 20 patients with insulin-dependent or non-insulin dependent diabetes mellitus (IDDM/NIDDM) and 39 non-diabetic (CTR) patients, myocardial markers of oxidative stress, vasoactive proteins, endothelial nitric oxide synthase …

Auswirkungen von Umweltrisikofaktoren wie Lärm und Luftverschmutzung auf die psychische Gesundheit: Was wissen wir?

ZusammenfassungImmer mehr Studien unterstreichen die Rolle von Lärm und Luftverschmutzung als bedeutsame Umweltrisikofaktoren. Ungeklärt ist, welche Einflüsse Lärm und Luftverschmutzung auf die psychische Gesundheit ausüben. Aktuelle Studienergebnisse zeigen, dass Umgebungslärm (vor allem Verkehrslärm) und verschiedene Bestandteile von Luftverschmutzung (vor allem Feinstaub) das Risiko für psychische Erkrankungen wie Depressionen, Angststörungen, Psychosen und Suizid erhöhen können. Pathophysiologische Mechanismen umfassen sowohl biologische (wie oxidativen Stress und Inflammation) als auch psychosoziale Faktoren (wie mentalen Stress). Umweltrisikofaktoren wie Lärm und Luftverschmutzung kön…

Differential effects of organic nitrates on endothelial progenitor cells are determined by oxidative stress

Comparison of Direct and Indirect Antioxidant Effects of Linagliptin (BI 1356, ONDERO) with other Gliptins – Evidence for Anti-inflammatory Properties of Linagliptin

The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity.

Objective In diabetes, vascular dysfunction is characterized by impaired endothelial function due to increased oxidative stress. Empagliflozin, as a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), offers a novel approach for the treatment of type 2 diabetes by enhancing urinary glucose excretion. The aim of the present study was to test whether treatment with empagliflozin improves endothelial dysfunction in type I diabetic rats via reduction of glucotoxicity and associated vascular oxidative stress. Methods Type I diabetes in Wistar rats was induced by an intravenous injection of streptozotocin (60 mg/kg). One week after injection empagliflozin (10 and 30 mg/kg/d) was adminis…

New Therapeutic Implications of Endothelial Nitric Oxide Synthase (eNOS) Function/Dysfunction in Cardiovascular Disease

The Global Burden of Disease Study identified cardiovascular risk factors as leading causes of global deaths and life years lost. Endothelial dysfunction represents a pathomechanism that is associated with most of these risk factors and stressors, and represents an early (subclinical) marker/predictor of atherosclerosis. Oxidative stress is a trigger of endothelial dysfunction and it is a hall-mark of cardiovascular diseases and of the risk factors/stressors that are responsible for their initiation. Endothelial function is largely based on endothelial nitric oxide synthase (eNOS) function and activity. Likewise, oxidative stress can lead to the loss of eNOS activity or even “uncoupli…

Nebivolol inhibits superoxide formation by NADPH oxidase and endothelial dysfunction in angiotensin II-treated rats.

Nebivolol is a β 1 -receptor antagonist with vasodilator and antioxidant properties. Because the vascular NADPH oxidase is an important superoxide source, we studied the effect of nebivolol on endothelial function and NADPH oxidase activity and expression in the well-characterized model of angiotensin II–induced hypertension. Angiotensin II infusion (1 mg/kg per day for 7 days) caused endothelial dysfunction in male Wistar rats and increased vascular superoxide as detected by lucigenin-derived chemiluminescence, as well as dihydroethidine staining. Vascular NADPH oxidase activity, as well as expression at the mRNA and protein level, were markedly upregulated, as well as NOS III uncoupled, …

Platelet-localized FXI promotes a vascular coagulation-inflammatory circuit in arterial hypertension

Multicellular interactions of platelets, leukocytes, and the blood vessel wall support coagulation and precipitate arterial and venous thrombosis. High levels of angiotensin II cause arterial hypertension by a complex vascular inflammatory pathway that requires leukocyte recruitment and reactive oxygen species production and is followed by vascular dysfunction. We delineate a previously undescribed, proinflammatory coagulation-vascular circuit that is a major regulator of vascular tone, blood pressure, and endothelial function. In mice with angiotensin II-induced hypertension, tissue factor was up-regulated, as was thrombin-dependent endothelial cell vascular cellular adhesion molecule 1 ex…

Number of nitrate groups determines reactivity and potency of organic nitrates: a proof of concept study in ALDH-2−/− mice

Background and purpose: Mitochondrial aldehyde dehydrogenase (ALDH-2) has been shown to provide a pathway for bioactivation of organic nitrates and to be prone to desensitization in response to highly potent, but not to less potent, nitrates. We therefore sought to support the hypothesis that bioactivation by ALDH-2 critically depends on the number of nitrate groups within the nitrovasodilator. Experimental approach: Nitrates with one (PEMN), two (PEDN; GDN), three (PETriN; glyceryl trinitrate, GTN) and four (pentaerithrityl tetranitrate, PETN) nitrate groups were investigated. Vasodilatory potency was measured in isometric tension studies using isolated aortic segments of wild type (WT) an…

Comparison of DPP‐4 inhibition versus GLP‐1 analogue supplementation on survival and vascular complications in experimental sepsis (145.2)

Background: Dipeptidyl peptidase [DPP]-4 inhibitors are a new class of drug for the treatment of hyperglycemia and recent studies revealed anti-inflammatory effects of these gliptins in experimenta...

Virtual issue by COST Action BM1203 (EU-ROS) "Emerging concepts in redox biology and oxidative stress".

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Unique Features of the Low Molecular Weight Probe Salicylaldehyde in the Detection of Nanomolar Peroxynitrite Fluxes

Impairment of the extrusion transporter for asymmetric dimethyl-L-arginine: a novel mechanism underlying vasospastic angina.

Abstract A 37-year old male patient presented with frequent angina attacks (up to 40/day) largely resistant to classical vasodilator therapy. The patient showed severe coronary and peripheral endothelial dysfunction, increased platelet aggregation and increased platelet-derived superoxide production. The endothelial nitric oxide synthase (eNOS)-inhibitor N G -nitro- l -arginine methyl ester (L-NAME) reduced superoxide formation in platelets identifying “uncoupled” eNOS as a superoxide source. Oral l -arginine normalized coronary and peripheral endothelial dysfunction and reduced platelet aggregation and eNOS-derived superoxide production. Plasma concentrations of the endogenous NOS inhibito…

Dinitrosyl-iron triggers apoptosis in Jurkat cells despite overexpression of Bcl-2

Cells expressing the cytokine-inducible NO synthase are known to trigger apoptosis in neighboring cells. Paramagnetic dinitrosyl nonheme iron complexes (DNIC) were found in tumor tissue about 40 years ago; however, the role of these NO(+)-bearing species is not completely understood. In the human Jurkat leukemia cell line, the application of the model complex DNIC-thiosulfate (50-200 microM) induced apoptosis (defined by phosphatidylserine externalization) in a concentration- and time-dependent manner. In Jurkat cells, the pan-caspase inhibitor, zVADfmk (50 microM), and/or stable transfection of antiapoptotic protein, Bcl-2, was unable to afford protection against DNIC-induced apoptosis. Th…

Vascular Dysfunction in Streptozotocin-Induced Experimental Diabetes Strictly Depends on Insulin Deficiency

<i>Objective:</i> In previous studies we and others have shown that streptozotocin (STZ)-induced diabetes in rats is associated with vascular oxidative stress and dysfunction. In the present study, we sought to determine whether vascular dysfunction and oxidative stress strictly depend on insulin deficiency. <i>Methods:</i> The effects of insulin (2.5 U/day s.c., 2 weeks) therapy on vascular disorders in STZ-induced (60 mg/kg i.v., 8 weeks) diabetes mellitus (type I) were studied in Wistar rats. The contribution of NADPH oxidase to overall oxidative stress was investigated by in vivo (30 mg/kg/day s.c., 4 days) and in vitro treatment with apocynin. <i>Results:&…

Loss of Nrf2 in bone marrow-derived macrophages impairs antigen-driven CD8+ T cell function by limiting GSH and Cys availability

NF-E2-related factor 2 (Nrf2), known to protect against reactive oxygen species, has recently been reported to resolve acute inflammatory responses in activated macrophages. Consequently, disruption of Nrf2 promotes a proinflammatory macrophage phenotype. In the current study, we addressed the impact of this macrophage phenotype on CD8(+) T cell activation by using an antigen-driven coculture model consisting of Nrf2(-/-) and Nrf2(+/+) bone marrow-derived macrophages (BMDMΦ) and transgenic OT-1 CD8(+) T cells. OT-1 CD8(+) T cells encode a T cell receptor that specifically recognizes MHC class I-presented ovalbumin OVA(257-264) peptide, thereby causing a downstream T cell activation. Interes…

eNOS Uncoupling in Cardiovascular Diseases - the Role of Oxidative Stress and Inflammation

Many cardiovascular diseases and drug-induced complications are associated with - or even based on - an imbalance between the formation of reactive oxygen and nitrogen species (RONS) and antioxidant enzymes catalyzing the break-down of these harmful oxidants. According to the “kindling radical” hypothesis, the formation of RONS may trigger in certain conditions the activation of additional sources of RONS. According to recent reports, vascular dysfunction in general and cardiovascular complications such as hypertension, atherosclerosis and coronary artery diseases may be connected to inflammatory processes. The present review is focusing on the uncoupling of endothelial nitric oxide synthas…

Increased Circulating Levels of 3-Nitrotyrosine Autoantibodies

3-nitrotyrosine formation is an oxidative protein modification that was first discovered in vivo in the early 1990s by Beckman and colleagues.1,2 The biological relevance of this process was extensively investigated in the subsequent years and further facilitated by the development of 3-nitrotyrosine–specific antibodies.3 Protein tyrosine nitration is mainly mediated by 3 biochemical processes (Figure): (1) by peroxynitrite (ONOO−) formation,4–6 the reaction product of nitric oxide (•NO) and superoxide (•O2−); (2) by a (myelo)peroxidase-catalyzed nitrogen dioxide radical (•NO2) formation from hydrogen peroxide and nitrite;7,8 and (3) by a nonspecific formation of the nitrogen dioxide radica…

Monitoring White Blood Cell Mitochondrial Aldehyde Dehydrogenase Activity: Implications for Nitrate Therapy in Humans

Recent animal data suggest that reduced lipoic acid (LA) prevents oxidative inhibition of the nitrate bioactivating enzyme, the mitochondrial aldehyde dehydrogenase (ALDH-2), and that pentaerythritol tetranitrate (PETN) does not induce nitrate tolerance because of its intrinsic antioxidative properties, thereby preserving ALDH-2 activity. We sought to determine whether ALDH-2 activity in circulating white blood cells (WBCs) can be used to monitor nitrate tolerance and whether LA can prevent nitroglycerin tachyphylaxis in humans. Eight healthy male volunteers received, in randomized order, a single dose of glyceryl trinitrate (GTN; 0.8 mg), PETN (80 mg), or GTN plus LA (600 mg) orally. GTN (…

Nitroglycerin-induced cardioprotection is endothelial nitric oxide synthase- dependent

Purpose We sought to evaluate the contribution of the endogenous NO pathway to the cardioprotective action of nitroglycerin (NTG). Methods and Results Anesthetized rabbits were subjected to 30-min myocardial ischemia (isc) and 3-h reperfusion (rep) and randomized into: Control group (no further intervention); PostC group (application of 8 cycles 30-sec isc/rep) and NTG treated group (2 μg/kg-1/min-1 IV bolus) for 65 min starting 10 min prior to rep. In additional groups, pharmacological inhibitors of NOS, nNOS, iNOS, PI3K, adenosine receptors and PKG were administrated with or without NTG. The infarcted (I) to risk (R) ratio was estimated. In a second experimental series tissue samples were…

In vitro and in vivo characterization of a new organic nitrate hybrid drug covalently bound to pioglitazone.

<b><i>Background/Aims:</i></b> Organic nitrates represent a group of nitrovasodilators that are clinically used for the treatment of ischemic heart disease. The new compound CLC-3000 is an aminoethyl nitrate (AEN) derivative of pioglitazone, a thiazolidinedione antidiabetic agent combining the peroxisome proliferator-activated receptor γ agonist activity of pioglitazone with the NO-donating activity of the nitrate moiety. <b><i>Methods:</i></b> In vitro and in vivo characterization was performed by isometric tension recording, platelet function, bleeding time and detection of oxidative stress. <b><i>Results:</i></…

Endothelial Dysfunction in Tristetraprolin-deficient Mice Is Not Caused by Enhanced Tumor Necrosis Factor-α Expression

Cardiovascular events are important co-morbidities in patients with chronic inflammatory diseases like rheumatoid arthritis. Tristetraprolin (TTP) regulates pro-inflammatory processes through mRNA destabilization and therefore TTP-deficient mice (TTP(-/-) mice) develop a chronic inflammation resembling human rheumatoid arthritis. We used this mouse model to evaluate molecular signaling pathways contributing to the enhanced atherosclerotic risk in chronic inflammatory diseases. In the aorta of TTP(-/-) mice we observed elevated mRNA expression of known TTP targets like tumor necrosis factor-α (TNF-α) and macrophage inflammatory protein-1α, as well as of other pro-atherosclerotic mediators, l…

Time‐dependent induction of vascular oxidative stress, inflammation, endothelial dysfunction and high blood pressure by aircraft noise exposure in mice

Targeting vascular (endothelial) dysfunction

Abstract Cardiovascular diseases are major contributors to global deaths and disability-adjusted life years, with hypertension a significant risk factor for all causes of death. The endothelium that lines the inner wall of the vasculature regulates essential haemostatic functions, such as vascular tone, circulation of blood cells, inflammation and platelet activity. Endothelial dysfunction is an early predictor of atherosclerosis and future cardiovascular events. We review the prognostic value of obtaining measurements of endothelial function, the clinical techniques for its determination, the mechanisms leading to endothelial dysfunction and the therapeutic treatment of endothelial dysfunc…

Bevölkerungsbezogene psychische Gesundheit als Schlüsselfaktor im Umgang mit COVID-19

Zusammenfassung Ziel Das Ziel des Beitrages besteht darin, auf die bedeutsame Rolle der Prävention und Reduktion der psychischen Belastungen in der Allgemeinbevölkerung und in sensiblen Gruppen im Rahmen der Coronavirus-Krankheit-2019 (COVID-19) -Pandemie hinzuweisen. Methodik Der vorliegende Beitrag umfasst die Analyse und Bewertung von Studien und Empfehlungen von Organisationen wie der Weltgesundheitsorganisation (WHO), die die bevölkerungsbezogenen psychischen Auswirkungen von Epi-/Pandemien und deren Einfluss auf den weiteren Verlauf untersucht haben. Ergebnisse Angstbedingte Verhaltensweisen können sich negativ auf den Verlauf von Epidemien auswirken. Im Rahmen vergangener Ausbrüche v…

Chronic occupational noise exposure: Effects on DNA damage, blood pressure, and serum biochemistry

Abstract Noise levels experienced by industrial workers may cause both auditory and non-auditory harmful effects. We have studied the effects of chronic industrial noise exposure on DNA damage, blood pressure, and serum biochemistry in factory workers. Male workers (109 individuals) in three parts of a food factory in Shahroud, Iran were enrolled as the exposed group and male office workers (123 individuals) were the unexposed control group. Noise exposure was measured (dosimetry) and the comet assay was used to evaluate DNA damage in peripheral blood mononuclear cells. Glutathione peroxidase (GPx) and ceruloplasmin (Cp) levels were measured in serum samples. GPx levels, systolic and diasto…

Conversion of biliverdin to bilirubin by biliverdin reductase contributes to endothelial cell protection by heme oxygenase-1—evidence for direct and indirect antioxidant actions of bilirubin

Heme oxygenase-1 (HO-1) is highly protective in various pathophysiological states such as cardiovascular and neurodegenerative diseases. HO-1-derived bilirubin is an efficient scavenger of reactive oxygen and nitrogen species (RONS). It remains to determine whether conversion of biliverdin to bilirubin is an essential step for HO-1-conferred protection of endothelial cells. RONS scavenging activities of biliverdin versus bilirubin were assessed by different RONS generating systems and detection techniques. We also silenced the biliverdin reductase (BVR) or HO-1 gene in cultured primary human endothelial cells (HUVECs) and measured the effect on RONS formation upon stimulation with lipopolys…

Normalization of endothelial dysfunction and vascular oxidative stress by chronic atorvastatin treatment in a rat model of streptozotocin-induced diabetes mellitus (type I)

Exploiting the Pleiotropic Antioxidant Effects of Established Drugs in Cardiovascular Disease.

Cardiovascular disease is a leading cause of death and reduced quality of life worldwide. Arterial vessels are a primary target for endothelial dysfunction and atherosclerosis, which is accompanied or even driven by increased oxidative stress. Recent research in this field identified different sources of reactive oxygen and nitrogen species contributing to the pathogenesis of endothelial dysfunction. According to lessons from the past, improvement of endothelial function and prevention of cardiovascular disease by systemic, unspecific, oral antioxidant therapy are obviously too simplistic an approach. Source- and cell organelle-specific antioxidants as well as activators of intrinsic antiox…

Endogenous peroxynitrite modulates PGHS-1–dependent thromboxane A2 formation and aggregation in human platelets

Aggregation of activated platelets is considerably mediated by the autocrine action of thromboxane A2 (TxA2) which is formed in a prostaglandin endoperoxide H2 synthase-1 (PGHS-1 or COX-1)-dependent manner. The activity of PGHS-1 can be stimulated by peroxides, an effect termed "peroxide tone", that renders PGHS-1 the key regulatory enzyme in the formation of TxA2. Activated platelets release nitric oxide (*NO) and superoxide (O*2) but their interactions with the prostanoid pathway have been controversially discussed in platelet physiology and pathophysiology. The current study demonstrates that endogenously formed peroxynitrite at nanomolar concentrations, originating from the interaction …

Anti-oxidative effects in response to pentaerithrityl tetranitrate (PETN) treatment are mediated by heme oxygenase-1 and ferritin induction and prevent the development of nitrate tolerance and cross-tolerance in vivo

Nitroglycerin-induced endothelial dysfunction and tolerance involve adverse phosphorylation and S-glutathionylation of endothelial nitric oxide synthase — Beneficial effects of therapy with the AT1-receptor blocker telmisartan

Continuous administration of nitroglycerin (GTN) causes tolerance and endothelial dysfunction by inducing reactive oxygen species (ROS) production from various enzymatic sources, such as mitochondria, NADPH oxidase, and an uncoupled endothelial nitric oxide synthase (eNOS). In the present study, we tested the effects of type 1 angiotensin (AT(1))-receptor blockade with telmisartan on GTN-induced endothelial dysfunction in particular on eNOS phosphorylation and S-glutathionylation sites and the eNOS cofactor synthesizing enzyme GTP-cyclohydrolase I.Wistar rats were treated with telmisartan (2.7 or 8 mg/kg per day PO for 10 days) and with GTN (50 mg/kg per day SC for 3 days). Aortic eNOS phos…

Manganese superoxide dismutase and aldehyde dehydrogenase deficiency increase mitochondrial oxidative stress and aggravate age-dependent vascular dysfunction.

AimsImbalance between pro- and antioxidant species (e.g. during aging) plays a crucial role for vascular function and is associated with oxidative gene regulation and modification. Vascular aging is associated with progressive deterioration of vascular homeostasis leading to reduced relaxation, hypertrophy, and a higher risk of thrombotic events. These effects can be explained by a reduction in free bioavailable nitric oxide that is inactivated by an age-dependent increase in superoxide formation. In the present study, mitochondria as a source of reactive oxygen species (ROS) and the contribution of manganese superoxide dismutase (MnSOD, SOD-2) and aldehyde dehydrogenase (ALDH-2) were inves…

Development of an Analytical Assay for Electrochemical Detection and Quantification of Protein-Bound 3-Nitrotyrosine in Biological Samples and Comparison with Classical, Antibody-Based Methods.

Reactive oxygen and nitrogen species (RONS) cause oxidative damage, which is associated with endothelial dysfunction and cardiovascular disease, but may also contribute to redox signaling. Therefore, their precise detection is important for the evaluation of disease mechanisms. Here, we compared three different methods for the detection of 3-nitrotyrosine (3-NT), a marker of nitro-oxidative stress, in biological samples. Nitrated proteins were generated by incubation with peroxynitrite or 3-morpholino sydnonimine (Sin-1) and subjected to total hydrolysis using pronase, a mixture of different proteases. The 3-NT was then separated by high performance liquid chromatography (HPLC) and quantifi…

AT1-receptor blockade by telmisartan upregulates GTP-cyclohydrolase I and protects eNOS in diabetic rats.

Several enzymatic sources of reactive oxygen species (ROS) were described as potential reasons of eNOS uncoupling in diabetes mellitus. In the present study, we investigated the effects of AT1-receptor blockade with chronic telmisartan (25 mg/kg/day, 6.5 weeks) therapy on expression of the BH4-synthesizing enzyme GTP-cyclohydrolase I (GCH-I), eNOS uncoupling, and endothelial dysfunction in streptozotocin (STZ, 60 mg/kg iv, 7 weeks)-induced diabetes mellitus (type I). Telmisartan therapy did not modify blood glucose and body weight. Aortas from diabetic animals had vascular dysfunction as revealed by isometric tension studies (acetylcholine and nitroglycerin potency). Vascular and cardiac RO…

Short‐term e‐cigarette vapor exposure causes vascular oxidative stress and dysfunction ‐ evidence for a close connection to brain damage and a key role of the phagocytic NADPH oxidase (NOX‐2)

Nitric Oxide Reductase (P450nor) from Fusarium oxysporum

Mitochondrial oxidative stress and nitrate tolerance – comparison of nitroglycerin and pentaerithrityl tetranitrate in Mn-SOD+/- mice

Abstract Background Chronic therapy with nitroglycerin (GTN) results in a rapid development of nitrate tolerance which is associated with an increased production of reactive oxygen species (ROS). According to recent studies, mitochondrial ROS formation and oxidative inactivation of the organic nitrate bioactivating enzyme mitochondrial aldehyde dehydrogenase (ALDH-2) play an important role for the development of nitrate and cross-tolerance. Methods Tolerance was induced by infusion of wild type (WT) and heterozygous manganese superoxide dismutase mice (Mn-SOD+/-) with ethanolic solution of GTN (12.5 μg/min/kg for 4 d). For comparison, the tolerance-free pentaerithrityl tetranitrate (PETN, 1…

Peripheral artery disease, redox signaling, oxidative stress – Basic and clinical aspects

Reactive oxygen and nitrogen species (ROS and RNS, e.g. H2O2, nitric oxide) confer redox regulation of essential cellular signaling pathways such as cell differentiation, proliferation, migration and apoptosis. At higher concentrations, ROS and RNS lead to oxidative stress and oxidative damage of biomolecules (e.g. via formation of peroxynitrite, fenton chemistry). Peripheral artery disease (PAD) is characterized by severe ischemic conditions in the periphery leading to intermittent claudication and critical limb ischemia (end stage). It is well known that redox biology and oxidative stress play an important role in this setting. We here discuss the major pathways of oxidative stress and re…

Glutathione Peroxidase-1 Deficiency Potentiates Dysregulatory Modifications of Endothelial Nitric Oxide Synthase and Vascular Dysfunction in Aging

Recently, we demonstrated that gene ablation of mitochondrial manganese superoxide dismutase and aldehyde dehydrogenase-2 markedly contributed to age-related vascular dysfunction and mitochondrial oxidative stress. The present study has sought to investigate the extent of vascular dysfunction and oxidant formation in glutathione peroxidase-1–deficient ( GPx-1 −/− ) mice during the aging process with special emphasis on dysregulation (uncoupling) of the endothelial NO synthase. GPx-1 −/− mice on a C57 black 6 (C57BL/6) background at 2, 6, and 12 months of age were used. Vascular function was significantly impaired in 12-month-old GPx-1 −/− -mice as compared with age-matched controls. Oxidan…

Exacerbation of adverse cardiovascular effects of aircraft noise in an animal model of arterial hypertension

Arterial hypertension is the most important risk factor for the development of cardiovascular disease. Recently, aircraft noise has been shown to be associated with elevated blood pressure, endothelial dysfunction, and oxidative stress. Here, we investigated the potential exacerbated cardiovascular effects of aircraft noise in combination with experimental arterial hypertension. C57BL/6J mice were infused with 0.5 mg/kg/d of angiotensin II for 7 days, exposed to aircraft noise for 7 days at a maximum sound pressure level of 85 dB(A) and a mean sound pressure level of 72 dB(A), or subjected to both stressors. Noise and angiotensin II increased blood pressure, endothelial dysfunction, oxidati…

Redox regulation of cardiovascular inflammation – Immunomodulatory function of mitochondrial and Nox-derived reactive oxygen and nitrogen species

Oxidative stress is a major hallmark of cardiovascular diseases although a causal link was so far not proven by large clinical trials. However, there is a close association between oxidative stress and inflammation and increasing evidence for a causal role of (low-grade) inflammation for the onset and progression of cardiovascular diseases, which may serve as the missing link between oxidative stress and cardiovascular morbidity and mortality. With the present review we would like to highlight the multiple redox regulated pathways in inflammation, discuss the sources of reactive oxygen and nitrogen species that are of interest for these processes and finally discuss the importance of angiot…

Regulation of NADPH oxidase-mediated superoxide production by acetylation and deacetylation

Oral treatment of apolipoprotein E-knockout (ApoE-KO) mice with the putative sirtuin 1 (SIRT1) activator resveratrol led to a reduction of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity in the heart. In contrast, the SIRT1 inhibitor EX527 enhanced the superoxide production in isolated human polymorphonuclear granulocytes. In human monocytic THP-1 cells, phorbol ester-stimulated superoxide production was enhanced by inhibitors of histone deacetylases (HDACs; including quisinostat, trichostatin A (TSA), PCI34051, and tubastatin A) and decreased by inhibitors of histone acetyltransferases [such as garcinol, curcumin, and histone acetyltransferase (HAT) Inhibitor II]. Thes…

The Oxidative Stress Concept of Nitrate Tolerance and the Antioxidant Properties of Hydralazine

The hemodynamic and anti-ischemic effects of nitroglycerin (NTG) are rapidly blunted as a result of the development of nitrate tolerance. With initiation of NTG therapy, it is possible to detect neurohormonal activation and intravascular volume expansion. These so-called pseudotolerance mechanisms may compromise the vasodilatory effects of NTG. Long-term nitrate treatment also is associated with decreased vascular responsiveness caused by changes in intrinsic mechanisms of the tolerant vasculature itself. According to the oxidative stress concept, increased vascular superoxide (O 2 − ) production and an increased sensitivity to vasoconstrictors secondary to activation of protein kinase C co…

LSC Abstract – Lung-derived prostacyclin (PGI) in endothelial dysfunction in db/db mice

Aim: Increased risk of pulmonary hypertension and not clear response of pulmonary endothelium to diabetes were reasons to compare nitric oxide (NO) and PGI-dependent function in pulmonary and systemic circulation in diabetes type II. Methods: In fasted db mice (male, 20 weeks) we compared the function of pulmonary (isolated perfused lung-IPL) and aortic endothelium (wire myograph). It was supported by determination of nitrite(NO 2 - )/nitrate(NO 3 - ), PGI production, immunostaining (IMS) and western blot. Results: In diabetic IPL NO-dependent modulation of hypoxic pulmonary vasoconstriction was impaired but filtration coefficient increased; response to U46619 was enhanced; cumulative gener…

Molecular Mechanisms of the Crosstalk Between Mitochondria and NADPH Oxidase Through Reactive Oxygen Species—Studies in White Blood Cells and in Animal Models

Aims: Oxidative stress is involved in the development of cardiovascular disease. There is a growing body of evidence for a crosstalk between different enzymatic sources of oxidative stress. With the present study, we sought to determine the underlying crosstalk mechanisms, the role of the mitochondrial permeability transition pore (mPTP), and its link to endothelial dysfunction. Results: NADPH oxidase (Nox) activation (oxidative burst and translocation of cytosolic Nox subunits) was observed in response to mitochondrial reactive oxygen species (mtROS) formation in human leukocytes. In vitro, mtROS-induced Nox activation was prevented by inhibitors of the mPTP, protein kinase C, tyrosine kin…

Stimulation of the AT2 receptor reduced atherogenesis in ApoE−/−/AT1A−/− double knock out mice

AT1 receptor blockers (ARB) and in part ACE inhibitors (ACI) potentially exert beneficial effects on atherogenesis independent of AT1 receptor inhibition. These pleiotropic effects might be related to angiotensin II mediated activation of the AT2 receptor. To analyze this hypothesis we investigated the development of atherosclerosis and the role of ACIs and ARBs in apolipoprotein E-deficient (ApoE(-/-)) mice and in ApoE/AT1A receptor double knockout mice (ApoE(-/-)/AT1A(-/-)). ApoE(-/-) mice and ApoE(-/-)/AT1A(-/-) mice were fed cholesterol-rich diet for 7 weeks. Vascular oxidative stress, endothelial dysfunction, and atherosclerotic lesion formation were evident in ApoE(-/-) mice, but were…

Response to I. Batinic-Haberle et al.

Letter to the editor.-- et al.

Cyclooxygenase 2-selective and nonselective nonsteroidal anti-inflammatory drugs induce oxidative stress by up-regulating vascular NADPH oxidases.

Cyclooxygenase 2-selective inhibitors (coxibs) and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increase in cardiovascular events. The current study was designed to test the effect of coxibs and nonselective NSAIDs on vascular superoxide and nitric oxide (NO) production. mRNA expression of endothelial NO synthase (eNOS) and of the vascular NADPH oxidases was studied in spontaneously hypertensive rats (SHR) and in human endothelial cells. The expression of Nox1, Nox2, Nox4, and p22phox was increased markedly by the nonselective NSAIDs diclofenac or naproxen and moderately by rofecoxib or celecoxib in the aorta and heart of SHR. The up-regulation of NADPH …

Non-Hemodynamic Effects of Organic Nitrates and the Distinctive Characteristics of Pentaerithrityl Tetranitrate

Organic nitrates are among the oldest and yet most commonly employed drugs in the long-term therapy of coronary artery disease and congestive heart failure. While they have long been used in clinical practice, our understanding of their mechanism of action and side effects remains incomplete. For instance, recent findings provide evidence of previously unanticipated, non-hemodynamic properties that include potentially beneficial mechanisms (such as the induction of a protective phenotype that mimics ischemic preconditioning), but also toxic effects (such as endothelial and autonomic dysfunction, rebound angina, tolerance). To date, the most commonly employed organic nitrates are isosorbide …

Contribution of airborne desert dust to air quality and cardiopulmonary disease

Glucagon-like peptide-1 receptor signalling reduces microvascular thrombosis, nitro-oxidative stress and platelet activation in endotoxaemic mice

Background and purpose Excessive inflammation in sepsis causes microvascular thrombosis and thrombocytopenia associated with organ dysfunction and high mortality. The present studies aimed to investigate whether inhibition of dipeptidyl peptidase-4 (DPP-4) and supplementation with glucagon-like peptide-1 (GLP-1) receptor agonists improved endotoxaemia-associated microvascular thrombosis via immunomodulatory effects. Experimental approach Endotoxaemia was induced in C57BL/6J mice by a single injection of LPS (17.5 mg kg-1 for survival and 10 mg kg-1 for all other studies). For survival studies, treatment was started 6 h after LPS injection. For all other studies, drugs were injected 48 h bef…

Differential effects of diabetes on the expression of the gp91phox homologues nox1 and nox4.

The nox2-dependent NADPH oxidase was shown to be a major superoxide source in vascular disease, including diabetes. Smooth muscle cells of large arteries lack the phagocytic gp91phox subunit of the enzyme; however, two homologues have been identified in these cells, nox1 and nox4. It remained to be established whether also increases in protein levels of the nonphagocytic NADPH oxidase contribute to increased superoxide formation in diabetic vessels. To investigate changes in the expression of these homologues, we measured their expression in aortic vessels of type I diabetic rats. Eight weeks after streptozotocin treatment, we found a doubling in nox1 protein expression, while the expressio…

The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats

Hyperglycemia associated with inflammation and oxidative stress is a major cause of vascular dysfunction and cardiovascular disease in diabetes. Recent data reports that a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i), empagliflozin (Jardiance®), ameliorates glucotoxicity via excretion of excess glucose in urine (glucosuria) and significantly improves cardiovascular mortality in type 2 diabetes mellitus (T2DM). The overarching hypothesis is that hyperglycemia and glucotoxicity are upstream of all other complications seen in diabetes. The aim of this study was to investigate effects of empagliflozin on glucotoxicity, β-cell function, inflammation, oxidative stress and endothel…

Explaining the phenomenon of nitrate tolerance.

During the last century, nitroglycerin has been the most commonly used antiischemic and antianginal agent. Unfortunately, after continuous application, its therapeutic efficacy rapidly vanishes. Neurohormonal activation of vasoconstrictor signals and intravascular volume expansion constitute early counter-regulatory responses (pseudotolerance), whereas long-term treatment induces intrinsic vascular changes, eg, a loss of nitrovasodilator-responsiveness (vascular tolerance). This is caused by increased vascular superoxide production and a supersensitivity to vasoconstrictors secondary to a tonic activation of protein kinase C. NADPH oxidase(s) and uncoupled endothelial nitric oxide synthase …

11,12-EET Stimulates the Association of BK Channel α and β1 Subunits in Mitochondria to Induce Pulmonary Vasoconstriction

In the systemic circulation, 11,12-epoxyeicosatrienoic acid (11,12-EET) elicits nitric oxide (NO)- and prostacyclin-independent vascular relaxation, partially through the activation of large conductance Ca(2+)-activated potassium (BK) channels. However, in the lung 11,12-EET contributes to hypoxia-induced pulmonary vasoconstriction. Since pulmonary artery smooth muscle cells also express BK channels, we assessed the consequences of BKβ(1) subunit deletion on pulmonary responsiveness to 11,12-EET as well as to acute hypoxia. In buffer-perfused mouse lungs, hypoxia increased pulmonary artery pressure and this was significantly enhanced in the presence of NO synthase (NOS) and cyclooxygenase (…

Circadian rhythms in ischaemic heart disease

Abstract Circadian rhythms are internal regulatory processes controlled by molecular clocks present in essentially every mammalian organ that temporally regulate major physiological functions. In the cardiovascular system, the circadian clock governs heart rate, blood pressure, cardiac metabolism, contractility, and coagulation. Recent experimental and clinical studies highlight the possible importance of circadian rhythms in the pathophysiology, outcome, or treatment success of cardiovascular disease, including ischaemic heart disease. Disturbances in circadian rhythms are associated with increased cardiovascular risk and worsen outcome. Therefore, it is important to consider circadian rhy…

Betulinic Acid Protects from Ischemia-Reperfusion Injury in the Mouse Retina

Ischemia/reperfusion (I/R) events are involved in the pathophysiology of numerous ocular diseases. The purpose of this study was to test the hypothesis that betulinic acid protects from I/R injury in the mouse retina. Ocular ischemia was induced in mice by increasing intraocular pressure (IOP) to 110 mm Hg for 45 min, while the fellow eye served as a control. One group of mice received betulinic acid (50 mg/kg/day p.o. once daily) and the other group received the vehicle solution only. Eight days after the I/R event, the animals were killed and the retinal wholemounts and optic nerve cross-sections were prepared and stained with cresyl blue or toluidine blue, respectively, to count cells in…

Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach

Systems medicine has a mechanism-based rather than a symptom- or organ-based approach to disease and identifies therapeutic targets in a nonhypothesis-driven manner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) by cross-validating its position in a protein-protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecular profiles suggests alterations of NRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome). This netw…

Pentaerithrityl tetranitrate improves angiotensin II induced vascular dysfunction via induction of heme oxygenase-1

The organic nitrate pentaerythritol tetranitrate is devoid of nitrate tolerance, which has been attributed to the induction of the antioxidant enzyme heme oxygenase (HO)-1. With the present study, we tested whether chronic treatment with pentaerythritol tetranitrate can improve angiotensin II–induced vascular oxidative stress and dysfunction. In contrast to isosorbide-5 mononitrate (75 mg/kg per day for 7 days), treatment with pentaerythritol tetranitrate (15 mg/kg per day for 7 days) improved the impaired endothelial and smooth muscle function and normalized vascular and cardiac reactive oxygen species production (mitochondria, NADPH oxidase activity, and uncoupled endothelial NO synthase)…

The AMP-Activated Protein Kinase Plays a Role in Antioxidant Defense and Regulation of Vascular Inflammation

Cardiovascular diseases represent the leading cause of global deaths and life years spent with a severe disability. Endothelial dysfunction and vascular oxidative stress are early precursors of atherosclerotic processes in the vascular wall, all of which are hallmarks in the development of cardiovascular diseases and predictors of future cardiovascular events. There is growing evidence that inflammatory processes represent a major trigger for endothelial dysfunction, vascular oxidative stress and atherosclerosis and clinical data identified inflammation as a cardiovascular risk factor on its own. AMP-activated protein kinase (AMPK) is a central enzyme of cellular energy balance and metaboli…

Oxidative Inhibition of the Mitochondrial Aldehyde Dehydrogenase Promotes Nitroglycerin Tolerance in Human Blood Vessels

Objectives We tested the hypothesis of whether an inhibition of the nitroglycerin (GTN) bioactivating enzyme mitochondrial aldehyde dehydrogenase (ALDH-2) contributes to GTN tolerance in human blood vessels. Background The hemodynamic effects of GTN are rapidly blunted by the development of tolerance, a phenomenon associated with increased formation of reactive oxygen species (ROS). Recent studies suggest that ROS-induced inhibition of ALDH-2 accounts for tolerance in animal models. Methods Segments of surgically removed arteria mammaria and vena saphena from patients undergoing coronary bypass surgery were used to examine the vascular responsiveness to GTN and the endothelium-dependent vas…

Nitrate therapy: new aspects concerning molecular action and tolerance.

Although the short-term vasodilatory properties of organic nitrates are potent and well known, a number of vascular and extravascular changes have been shown to compromise their hemodynamic effects on long-term administration. Among these changes, systemic phenomena such as neurohormonal activation and intravascular volume expansion1 as well as specific vascular changes such as increased vascular superoxide (O2·−) production,2 increased sensitivity to vasoconstrictors,3 and decreased responsiveness to nitric oxide (NO) donors4,5 have long been identified as playing a role. Several hypotheses have been proposed to explain these abnormalities, and over the last 15 years, our groups have focus…

Enhanced Age-Dependent ENOS Dysfunction and - Uncoupling in Glutathione Peroxidase-1-Deficient Mice

Regulation of Human Mitochondrial Aldehyde Dehydrogenase (ALDH-2) Activity by Electrophiles in Vitro

Recently, mitochondrial aldehyde dehydrogenase (ALDH-2) was reported to reduce ischemic damage in an experimental myocardial infarction model. ALDH-2 activity is redox-sensitive. Therefore, we here compared effects of various electrophiles (organic nitrates, reactive fatty acid metabolites, or oxidants) on the activity of ALDH-2 with special emphasis on organic nitrate-induced inactivation of the enzyme, the biochemical correlate of nitrate tolerance. Recombinant human ALDH-2 was overexpressed in Escherichia coli; activity was determined with an HPLC-based assay, and reactive oxygen and nitrogen species formation was determined by chemiluminescence, fluorescence, protein tyrosine nitration,…

Hydralazine is a powerful inhibitor of peroxynitrite formation as a possible explanation for its beneficial effects on prognosis in patients with congestive heart failure

The hemodynamic and anti-ischemic effects of nitroglycerin (GTN) are rapidly blunted as a result of the development of nitrate tolerance. Hydralazine has been shown to prevent tolerance in experimental and clinical studies, all of which may be at least in part secondary to antioxidant properties of this compound. The antioxidant effects of hydralazine were tested in cell free systems, cultured smooth muscle cells, isolated mitochondria, and isolated vessels. Inhibitory effects on the formation of superoxide and/or peroxynitrite formation were tested using lucigenin and L-012 enhanced chemiluminescence as well as DHE-fluorescence. The peroxynitrite scavenging properties were also assessed by…

Comparison of Linagliptin, Sitagliptin and Liraglutide Effects on Survival and Vascular Complications in Experimental Sepsis

Resveratrol and Vascular Function

Resveratrol increases the production of nitric oxide (NO) in endothelial cells by upregulating the expression of endothelial NO synthase (eNOS), stimulating eNOS enzymatic activity, and preventing eNOS uncoupling. At the same time, resveratrol inhibits the synthesis of endothelin-1 and reduces oxidative stress in both endothelial cells and smooth muscle cells. Pathological stimuli-induced smooth muscle cell proliferation, vascular remodeling, and arterial stiffness can be ameliorated by resveratrol as well. In addition, resveratrol also modulates immune cell function, inhibition of immune cell infiltration into the vascular wall, and improves the function of perivascular adipose tissue. All…

One Enzyme, Two Functions

The human enzyme paraoxonase-2 (PON2) has two functions, an enzymatic lactonase activity and the reduction of intracellular oxidative stress. As a lactonase, it dominantly hydrolyzes bacterial signaling molecule 3OC12 and may contribute to the defense against pathogenic Pseudomonas aeruginosa. By its anti-oxidative effect, PON2 reduces cellular oxidative damage and influences redox signaling, which promotes cell survival. This may be appreciated but also deleterious given that high PON2 levels reduce atherosclerosis but may stabilize tumor cells. Here we addressed the unknown mechanisms and linkage of PON2 enzymatic and anti-oxidative function. We demonstrate that PON2 indirectly but specif…

Accelerated Aging and Age-Related Diseases (CVD and Neurological) due to Air Pollution and Traffic Noise Exposure

The World Health Organization estimates that only approximately 25% of diversity in longevity is explained by genetic factors, while the other 75% is largely determined by interactions with the physical and social environments. Indeed, aging is a multifactorial process that is influenced by a range of environmental, sociodemographic, and biopsychosocial factors, all of which might act in concert to determine the process of aging. The global average life expectancy increased fundamentally over the past century, toward an aging population, correlating with the development and onset of age-related diseases, mainly from cardiovascular and neurological nature. Therefore, the identification of de…

Antioxidant effects of resveratrol in the cardiovascular system

The antioxidant effects of resveratrol (3,5,4'-trihydroxy-trans-stilbene) contribute substantially to the health benefits of this compound. Resveratrol has been shown to be a scavenger of a number of free radicals. However, the direct scavenging activities of resveratrol are relatively poor. The antioxidant properties of resveratrol in vivo are more likely to be attributable to its effect as a gene regulator. Resveratrol inhibits NADPH oxidase-mediated production of ROS by down-regulating the expression and activity of the oxidase. This polyphenolic compound reduces mitochondrial superoxide generation by stimulating mitochondria biogenesis. Resveratrol prevents superoxide production from un…

A new class of organic nitrates: investigations on bioactivation, tolerance and cross-tolerance phenomena

Background and purpose:  The chronic use of organic nitrates is limited by serious side effects including oxidative stress, nitrate tolerance and/or endothelial dysfunction. The side effects and potency of nitroglycerine depend on mitochondrial aldehyde dehydrogenase (ALDH-2). We sought to determine whether this concept can be extended to a new class of organic nitrates with amino moieties (aminoalkyl nitrates). Experimental approach:  Vasodilator potency of the organic nitrates, in vitro tolerance and in vivo tolerance (after continuous infusion for 3 days) were assessed in wild-type and ALDH-2 knockout mice by isometric tension studies. Mitochondrial oxidative stress was analysed by L-012…

Could E-cigarette vaping contribute to heart disease?

E-cigarettes have become a controversial topic. While their benefits are questioned by the scientific community, a part of the medical profession is still supporting them as an effective harm reduction tool for smoking cessation. The impact of E-cigarettes on the cardiovascular system is still elusive.We assessed results from animal, pre(clinical), and epidemiological studies to critically evaluate and synthesize evidence relevant to the cardiovascular effects of E-cigarettes. Animal studies have demonstrated that E-cigarette vapor exposure can cause endothelial and cardiac dysfunction. However, there have also been reports on the less harmful effects of E-cigarette vapor exposure in compar…

Gp91phox-containing NAD(P)H oxidase increases superoxide formation by doxorubicin and NADPH

Doxorubicin is a highly effective antineoplastic drug associated with a dose-dependent cardiotoxicity that may result in irreversible cardiomyopathy and heart failure. Gene variants of the superoxide-generating enzyme NAD(P)H oxidase have recently been associated with this phenotype. We investigated the mechanism of this association using lucigenin-enhanced chemiluminescence, spectrophotometry, electrochemical sensor, and electron paramagnetic resonance spectroscopy. Superoxide production was measured in female wild-type and NAD(P)H oxidase-deficient (gp91phox knockout) mice. The magnitude of the increase in superoxide production on the addition of doxorubicin was much higher in hearts of w…

Effects of clopidogrel vs. prasugrel vs. ticagrelor on endothelial function, inflammatory parameters, and platelet function in patients with acute coronary syndrome undergoing coronary artery stenting: a randomized, blinded, parallel study

Abstract Aims In a randomized, parallel, blinded study, we investigate the impact of clopidogrel, prasugrel, or ticagrelor on peripheral endothelial function in patients undergoing stenting for an acute coronary syndrome. Methods and results The primary endpoint of the study was the change in endothelium-dependent flow-mediated dilation (FMD) following stenting. A total of 90 patients (age 62 ± 9 years, 81 males, 22 diabetics, 49 non-ST elevation myocardial infarctions) were enrolled. There were no significant differences among groups in any clinical parameter. Acutely before stenting, all three drugs improved FMD without differences between groups (P = 0.73). Stenting blunted FMD in the cl…

B Lymphocyte-Deficiency in Mice Causes Vascular Dysfunction by Inducing Neutrophilia

B lymphocytes have been implicated in the development of insulin resistance, atherosclerosis and certain types of hypertension. In contrast to these studies, which were performed under pathological conditions, the present study provides evidence for the protective effect of B lymphocytes in maintaining vascular homeostasis under physiological conditions. In young mice not exposed to any known risk factors, the lack of B cells led to massive endothelial dysfunction. The vascular dysfunction in B cell-deficient mice was associated with an increased number of neutrophils in the circulating blood. Neutrophil depletion in B cell-deficient mice resulted in the complete normalization of vascular f…

Stimulatory TSH-Receptor Antibodies and Oxidative Stress in Graves Disease

CONTEXT: We hypothesized that TSH-receptor (TSHR) stimulating antibodies (TSAbs) are involved in oxidative stress mechanisms in patients with Graves disease (GD). METHODS: Nicotinamide adenine dinucleotide phosphate oxidase, isoform 2 (NOX2); oxidative parameters; and oxidative burst were measured in serum, urine, and whole blood from patients with GD and control subjects. Superoxide production was investigated in human embryonic kidney (HEK)-293 cells stably overexpressing the TSHR. Lipid peroxidation was determined by immunodot-blot analysis for protein-bound 4-hydroxy-2-nonenal (4-HNE) in human primary thyrocytes and HEK-293–TSHR cells. RESULTS: Serum NOX2 levels were markedly higher in …

Noise-Induced Vascular Dysfunction, Oxidative Stress, and Inflammation Are Improved by Pharmacological Modulation of the NRF2/HO-1 Axis

Vascular oxidative stress, inflammation, and subsequent endothelial dysfunction are consequences of traditional cardiovascular risk factors, all of which contribute to cardiovascular disease. Environmental stressors, such as traffic noise and air pollution, may also facilitate the development and progression of cardiovascular and metabolic diseases. In our previous studies, we investigated the influence of aircraft noise exposure on molecular mechanisms, identifying oxidative stress and inflammation as central players in mediating vascular function. The present study investigates the role of heme oxygenase-1 (HO-1) as an antioxidant response preventing vascular consequences following exposu…

L-citrulline ameliorates pathophysiology in a rat model of superimposed preeclampsia

AbstractPreeclampsia, characterized by hypertension, proteinuria, and fetal growth restriction, is one of the leading causes of maternal and perinatal mortality. By far, there is no effective pharmacological therapy for preeclampsia. The present study was conducted to investigate the effects of L-citrulline supplementation in Dahl salt-sensitive rat, a model of superimposed preeclampsia. Parental DSSR were treated with L-citrulline (2.5 g/L in drinking water) from the day of mating to the end of lactation period. Blood pressure of the rats was monitored throughout pregnancy and markers of preeclampsia were assessed. Endothelial function of the pregnant DSSR was assessed by wire myograph. L-…

Abstract 18540: Heme Oxygenase 1 Activity and Expression Suppresses a Proinflammatory Phenotype in Monocytes and Correlates With Endothelial Function in Mice and Humans

Background: Heme oxygenase-1 (HO-1) confers protection to the vasculature and suppresses inflammatory properties of monocytes and macrophages. It is unclear how HO-1 activity and expression determine the extent of vascular dysfunction in mice and humans. Methods and results: Decreasing HO activity was parallelled by decreasing aortic HO-1, eNOS and phospho-eNOS (ser1177) protein expression in HO-1 deficient mice, whereas aortic expression of nox2 showed a stepwise increase in HO-1+/- and HO-1-/- mice as compared to HO-1+/+ controls. Aortic superoxide formation increased depending on the extent of HO-1 deficiency and was blunted by the PKC inhibitor chelerythrine, indicating activation of t…

Aircraft noise exposure drives the activation of white blood cells and induces microvascular dysfunction in mice

Epidemiological studies showed that traffic noise has a dose-dependent association with increased cardiovascular morbidity and mortality. Whether microvascular dysfunction contributes significantly to the cardiovascular health effects by noise exposure remains to be established. The connection of inflammation and immune cell interaction with microvascular damage and functional impairment is also not well characterized. Male C57BL/6J mice or gp91phox−/y mice with genetic deletion of the phagocytic NADPH oxidase catalytic subunit (gp91phox or NOX-2) were used at the age of 8 weeks, randomly instrumented with dorsal skinfold chambers and exposed or not exposed to aircraft noise for 4 days. Pro…

Corrigendum to “European contribution to the study of ROS: A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)” [Redox Biol. 13 (2017) 94–162]

The European Cooperation in Science and Technology (COST) provides an ideal framework to establish multi-disciplinary research networks. COST Action BM1203 (EU-ROS) represents a consortium of researchers from different disciplines who are dedicated to providing new insights and tools for better understanding redox biology and medicine and, in the long run, to finding new therapeutic strategies to target dysregulated redox processes in various diseases. This report highlights the major achievements of EU-ROS as well as research updates and new perspectives arising from its members. The EU-ROS consortium comprised more than 140 active members who worked together for four years on the topics b…

Antioxidants in Translational Medicine.

This Open Access article is distributed under the terms of the Creative Commons Attribution Noncommercial License.-- et al.

Effects of Sodium dependent Glucose Transporter 2 (SGLT2) Inhibition with Empagliflozin on Oxidative Stress and Endothelial Dysfunction in STZ-Induced Type I Diabetic Rat

Effects of nitroglycerin or pentaerithrityl tetranitrate treatment on the gene expression in rat hearts: evidence for cardiotoxic and cardioprotective effects.

Nitroglycerin (NTG) and pentaerithrityl tetranitrate (PETN) are organic nitrates used in the treatment of angina pectoris, myocardial infarction, and congestive heart failure. Recent data show marked differences in the effects of NTG and PETN on the generation of reactive oxygen species. These differences are attributed to different effects of NTG and PETN on the expression of antioxidative proteins like the heme oxygenase-I. To analyze the expressional effects of NTG and PETN in a more comprehensive manner we performed whole genome expression profiling experiments using cardiac total RNA from NTG- or PETN-treated rats and DNA microarrays containing oligonucleotides representing 27,044 rat…

The potential of aldehyde dehydrogenase 2 as a therapeutic target in cardiovascular disease.

Mitochondrial aldehyde dehydrogenase (ALDH-2) plays a major role in the ethanol detoxification pathway by removing acetaldehyde. Therefore, ALDH-2 inhibitors such as disulfiram represent the first therapeutic targeting of ALDH-2 for alcoholism therapy. Areas covered: Recently, ALDH-2 was identified as an essential bioactivating enzyme of the anti-ischemic organic nitrate nitroglycerin, bringing ALDH-2 again into the focus of clinical interest. Mechanistic studies on the nitroglycerin bioactivation process revealed that during bioconversion of nitroglycerin and in the presence of reactive oxygen and nitrogen species the active site thiols of ALDH-2 are oxidized and the enzyme activity is los…

Effects of air pollution particles (ultrafine and fine particulate matter) on mitochondrial function and oxidative stress – Implications for cardiovascular and neurodegenerative diseases

Environmental pollution is a major cause of global mortality and burden of disease. All chemical pollution forms together may be responsible for up to 12 million annual excess deaths as estimated by the Lancet Commission on pollution and health as well as the World Health Organization. Ambient air pollution by particulate matter (PM) and ozone was found to be associated with an all-cause mortality rate of up to 9 million in the year 2015, with the majority being of cerebro- and cardiovascular nature (e.g. stroke and ischemic heart disease). Recent evidence suggests that exposure to airborne particles and gases contributes to and accelerates neurodegenerative diseases. Especially, airborne t…

Effects of tobacco cigarettes, e-cigarettes, and waterpipe smoking on endothelial function and clinical outcomes

Abstract Tobacco smoking is a leading cause of non-communicable disease globally and is a major risk factor for cardiovascular disease (CVD) and lung disease. Importantly, recent data by the World Health Organizations (WHO) indicate that in the last two decades global tobacco use has significantly dropped, which was largely driven by decreased numbers of female smokers. Despite such advances, the use of e-cigarettes and waterpipes (shisha, hookah, narghile) is an emerging trend, especially among younger generations. There is growing body of evidence that e-cigarettes are not a harm-free alternative to tobacco cigarettes and there is considerable debate as to whether e-cigarettes are saving …

P105. New findings on vasodilator potency, tachyphylaxis, and bioavailability of organic nitrates reveal: The tolerance-devoid clinical action of pentaerithrityl tetranitrate (PETN) is produced by its metabolites PEdiN and PEmonoN

Development and validation of an analytical assay for electrochemical detection and quantification of protein‐bound 3‐nitrotyrosine in biological samples and comparison with classical, antibody‐based methods

Inorganic Nitrate Therapy Improves Doxorubicin-Induced Cardiomyopathy

The anthracycline doxorubicin (DOX) is a potent and effective antineoplastic antibiotic agent widely used in the treatment of a broad range of forms of cancer. The clinical use of DOX is limited by cardiotoxicity, which increases dose dependently and may lead to dilated cardiomyopathy and clinical

Vascular Dysfunction in Nitroglycerininduced Nitrate Tolerance is Improved by Telmisartan Therapy — Suppression of the RAAS and PKC Pathway

The Role of DNA Damage in the Pathogenesis of Nitrate Tolerance

Chronic Therapy With Isosorbide-5-Mononitrate Causes Endothelial Dysfunction, Oxidative Stress and a Marked Increase in Vascular Endothelin-1 Expression

Aims Isosorbide-5-mononitrate (ISMN) is one of the most frequently used compounds in the treatment of coronary artery disease predominantly in the USA. However, ISMN was reported to induce endothelial dysfunction, which was corrected by vitamin C pointing to a crucial role of reactive oxygen species (ROS) in causing this phenomenon. We sought to elucidate the mechanism how ISMN causes endothelial dysfunction and oxidative stress in vascular tissue. Methods and results Male Wistar rats ( n = 69 in total) were treated with ISMN (75 mg/kg/day) or placebo for 7 days. Endothelin (ET) expression was determined by immunohistochemistry in aortic sections. Isosorbide-5-mononitrate infusion caused si…

Vascular Dysfunction in Experimental Diabetes Is Improved by Pentaerithrityl Tetranitrate but Not Isosorbide-5-Mononitrate Therapy

OBJECTIVE Diabetes is associated with vascular oxidative stress, activation of NADPH oxidase, and uncoupling of nitric oxide (NO) synthase (endothelial NO synthase [eNOS]). Pentaerithrityl tetranitrate (PETN) is an organic nitrate with potent antioxidant properties via induction of heme oxygenase-1 (HO-1). We tested whether treatment with PETN improves vascular dysfunction in the setting of experimental diabetes. RESEARCH DESIGN AND METHODS After induction of hyperglycemia by streptozotocin (STZ) injection (60 mg/kg i.v.), PETN (15 mg/kg/day p.o.) or isosorbide-5-mononitrate (ISMN; 75 mg/kg/day p.o.) was fed to Wistar rats for 7 weeks. Oxidative stress was assessed by optical methods and o…

Effects of clopidogrel, prasugrel and ticagrelor on endothelial function, inflammatory and oxidative stress parameters and platelet function in patients undergoing coronary artery stenting for an acute coronary syndrome : a randomised, prospective, controlled study

Introduction Particularly in the setting of acute coronary syndromes, the interplay between vascular and platelet function has been postulated to have direct clinical implications. The present trial is designed to test the effect of clopidogrel, prasugrel and ticagrelor on multiple parameters of vascular function, platelet aggregation, oxidative and inflammatory stress before and up to 4 weeks after coronary artery stenting. Methods and analysis The study is designed as a three-arm, parallel design, randomised, investigator-blinded study. Patients with unstable angina or non-ST elevation myocardial infarction undergoing coronary intervention with a drug-eluting stent will be randomised to r…

Crucial role for Nox2 and sleep deprivation in aircraft noise-induced vascular and cerebral oxidative stress, inflammation, and gene regulation

Abstract Aims Aircraft noise causes endothelial dysfunction, oxidative stress, and inflammation. Transportation noise increases the incidence of coronary artery disease, hypertension, and stroke. The underlying mechanisms are not well understood. Herein, we investigated effects of phagocyte-type NADPH oxidase (Nox2) knockout and different noise protocols (around-the-clock, sleep/awake phase noise) on vascular and cerebral complications in mice. Methods and results C57BL/6j and Nox2 −/− (gp91phox −/−) mice were exposed to aircraft noise (maximum sound level of 85 dB(A), average sound pressure level of 72 dB(A)) around-the-clock or during sleep/awake phases for 1, 2, and 4 days. Adverse effec…

Influence of mental stress and environmental toxins on circadian clocks : implications for redox regulation of the heart and cardioprotection

Risk factors in the environment such as air pollution and mental stress contribute to the development of chronic non-communicable disease. Air pollution was identified as the leading health risk factor in the physical environment, followed by water pollution, soil pollution/heavy metals/chemicals and occupational exposures, however neglecting the non-chemical environmental health risk factors (e.g. mental stress and noise). Epidemiological data suggest that environmental risk factors are associated with higher risk for cardiovascular, metabolic and mental diseases, including hypertension, heart failure, myocardial infarction, diabetes, arrhythmia, stroke, depression and anxiety disorders. W…

Heart healthy cities : Genetics loads the gun but the environment pulls the trigger

Abstract The world’s population is estimated to reach 10 billion by 2050 and 75% of this population will live in cities. Two-third of the European population already live in urban areas and this proportion continues to grow. Between 60% and 80% of the global energy use is consumed by urban areas, with 70% of the greenhouse gas emissions produced within urban areas. The World Health Organization states that city planning is now recognized as a critical part of a comprehensive solution to tackle adverse health outcomes. In the present review, we address non-communicable diseases with a focus on cardiovascular disease and the urbanization process in relation to environmental risk exposures inc…

In vivo analysis of noise dependent activation of white blood cells and microvascular dysfunction in mice

This article contains supporting information on data collection for the research article entitled “Aircraft noise exposure drives the activation of white blood cells and induces microvascular dysfunction in mice” by Eckrich et al. We found that noise-induced stress triggered microvascular dysfunction via involvement of innate immune-derived reactive oxygen species. In this article, we present the instrumentation of mice with dorsal skinfold chambers for in vivo microscopic imaging of blood flow, interaction of leukocytes with the vascular wall (also by fluorescent labelling of blood cells) and vessel diameter. In addition, we explain the preparation of cerebral arterioles for measurement of…

Environmental noise aggravates oxidative DNA damage, granulocyte oxidative burst and nitrate resistance in Ogg1−/− mice

Comparison of direct and indirect antioxidant effects of linagliptin with other gliptins — Evidence for antioxidant and antiinflammatory properties of linagliptin

NO donors. Part 16: investigations on structure-activity relationships of organic mononitrates reveal 2-nitrooxyethylammoniumnitrate as a high potent vasodilator.

The vasoactive properties of 14 organic mononitrates were investigated in vitro using PGF(2alpha)-precontracted porcine pulmonary arteries. A surprisingly wide range of vasorelaxant potencies was observed (pD(2): 3.36-7.50). Activities showed to be highly sensitive to the molecular structure and the substituents at the molecular carrier of the nitrate group. A correlation between lipophilicity and vasorelaxant potency could not be recognized. 2-Nitrooxyethylammoniumnitrate (1) was found to be slightly superior to the high potency trinitrate GTN.

Mechanisms underlying recoupling of eNOS by HMG-CoA reductase inhibition in a rat model of streptozotocin-induced diabetes mellitus

Abstract Objective HMG-CoA reductase inhibitors have been shown to upregulate GTP cyclohydrolase I (GTPCH-I), the key enzyme for tetrahydrobiopterin de novo synthesis and to normalize tetrahydrobiopterin levels in hyperglycemic endothelial cells. We sought to determine whether in vivo treatment with the HMG-CoA reductase inhibitor atorvastatin is able to upregulate the GTPCH-I, to recouple eNOS and to normalize endothelial dysfunction in an experimental model of diabetes mellitus. Methods and results In male Wistar rats, diabetes was induced by streptozotocin (STZ, 60mg/kg). In STZ rats, atorvastatin feeding (20mg/kg/d, 7 weeks), normalized vascular dysfunction as analyzed by isometric tens…

Betulinic acid protects against cerebral ischemia–reperfusion injury in mice by reducing oxidative and nitrosative stress

Increased production of reactive oxygen and nitrogen species following cerebral ischemia-reperfusion is a major cause for neuronal injury. In hypercholesterolemic apolipoprotein E knockout (ApoE-KO) mice, 2h of middle cerebral artery (MCA) occlusion followed by 22h of reperfusion led to an enhanced expression of NADPH oxidase subunits (NOX2, NOX4 and p22phox) and isoforms of nitric oxide synthase (neuronal nNOS and inducible iNOS) in the ischemic hemisphere compared with the non-ischemic contralateral hemisphere. This was associated with elevated levels of 3-nitrotyrosine, an indicator of peroxynitrite-mediated oxidative protein modification. Pre-treatment with betulinic acid (50mg/kg/day f…

Inhibition of Rac1 GTPase Decreases Vascular Oxidative Stress, Improves Endothelial Function, and Attenuates Atherosclerosis Development in Mice

Aims: Oxidative stress and inflammation contribute to atherogenesis. Rac1 GTPase regulates pro-oxidant NADPH oxidase activity, reactive oxygen species (ROS) formation, actin cytoskeleton organization and monocyte adhesion. We investigated the vascular effects of pharmacological inhibition of Rac1 GTPase in mice.Methods and Results: We treated wild-type and apolipoprotein E-deficient (ApoE−/−) mice with Clostridium sordellii lethal toxin (LT), a Rac1 inhibitor, and assessed vascular oxidative stress, expression and activity of involved proteins, endothelial function, macrophage infiltration, and atherosclerosis development. LT-treated wild-type mice displayed decreased vascular NADPH oxidase…

Regulation of vascular function and inflammation via cross talk of reactive oxygen and nitrogen species from mitochondria or nadph oxidase—implications for diabetes progression

Oxidative stress plays a key role for the development of cardiovascular, metabolic, and neurodegenerative disease. This concept has been proven by using the approach of genetic deletion of reactive oxygen and nitrogen species (RONS) producing, pro-oxidant enzymes as well as by the overexpression of RONS detoxifying, antioxidant enzymes leading to an amelioration of the severity of diseases. Vice versa, the development and progression of cardiovascular diseases is aggravated by overexpression of RONS producing enzymes as well as deletion of RONS detoxifying enzymes. We have previously identified cross talk mechanisms between different sources of RONS, which can amplify the oxidative stress-m…

Taking up the cudgels for the traditional reactive oxygen and nitrogen species detection assays and their use in the cardiovascular system

Reactive oxygen and nitrogen species (RONS such as H2O2, nitric oxide) confer redox regulation of essential cellular functions (e.g. differentiation, proliferation, migration, apoptosis), initiate and catalyze adaptive stress responses. In contrast, excessive formation of RONS caused by impaired break-down by cellular antioxidant systems and/or insufficient repair of the resulting oxidative damage of biomolecules may lead to appreciable impairment of cellular function and in the worst case to cell death, organ dysfunction and severe disease phenotypes of the entire organism. Therefore, the knowledge of the severity of oxidative stress and tissue specific localization is of great biological …

Traffic-related environmental risk factors and their impact on oxidative stress and cardiovascular health

Abstract The adverse effects of the environment on health are increasingly recognized. The WHO estimates that noise accounts for 1 million annually lost healthy life years in Western Europe due to increased incidence of hypertension, heart failure, myocardial infarction, and stroke. An even more severe health impact was reported for air pollution (e.g., PM2.5) accounting for up to 800,000 annual excess deaths in Europe. Adverse effects of air pollution are mechanistically better characterized, but there is still a great need to understand the pathophysiology of air pollution-induced cardiovascular disease, especially the potential synergistic effects together with noise. With the present bo…

Doxorubicin induces wide-spread transcriptional changes in the myocardium of hearts distinguishing between mice with preserved and impaired cardiac function

Abstract Aims Doxorubicin (DOX) is an important drug for the treatment of various tumor entities. However, the occurrence of heart failure limits its application. This study investigated differential gene expression profiles in the left and right ventricles of DOX treated mice with either preserved or impaired myocardial function. We provide new mechanistic insights into the pathophysiology of DOX-induced heart failure and have discovered pathways that counteract DOX-induced cardiotoxicity. Main methods We used in total 48 male mice and applied a chronic low dose DOX administration (5 mg/kg per injection, in total 20 mg/kg over 4 weeks) to induce heart failure. Echocardiographic parameters …

Nitroglycerin-Induced Endothelial Dysfunction and Tolerance Involve Adverse Phosphorylation and S -Glutathionylation of Endothelial Nitric Oxide Synthase

Objective— Continuous administration of nitroglycerin (GTN) causes tolerance and endothelial dysfunction by inducing reactive oxygen species (ROS) production from various enzymatic sources, such as mitochondria, NADPH oxidase, and an uncoupled endothelial nitric oxide synthase (eNOS). In the present study, we tested the effects of type 1 angiotensin (AT 1 )-receptor blockade with telmisartan on GTN-induced endothelial dysfunction in particular on eNOS phosphorylation and S -glutathionylation sites and the eNOS cofactor synthesizing enzyme GTP–cyclohydrolase I. Methods and Results— Wistar rats were treated with telmisartan (2.7 or 8 mg/kg per day PO for 10 days) and with GTN (50 mg/kg per d…

Long-term cardiovascular risk of e-cigarettes

Antagonization of IL-17A Attenuates Skin Inflammation and Vascular Dysfunction in Mouse Models of Psoriasis

Besides skin inflammation, patients with severe psoriasis suffer from an increased risk of cardiovascular mortality. IL-17A plays a central role in the development of psoriasis and might connect skin and vascular disease. The aim of this study was to clarify whether anti-IL-17A therapy could also ameliorate the vascular dysfunction associated with severe psoriasis. We analyzed three murine models with varying severities of psoriasis-like skin disease concerning their vascular function and inflammation: (i) K14-IL-17A(ind/+) mice with keratinocyte-specific IL-17A overexpression and an early-onset severe psoriasis-like phenotype; (ii) homozygous CD11c-IL-17A(ind/ind) and heterozygous CD11c-IL…

Chemical model systems for cellular nitros(yl)ation reactions.

S-nitros(yl)ation belongs to the redox-based posttranslational modifications of proteins but the underlying chemistry is controversial. In contrast to current concepts involving the autoxidation of nitric oxide ( • NO, nitrogen monoxide), we and others have proposed the formation of peroxynitrite (oxoperoxonitrate (1-)) as an essential intermediate. This requires low cellular fluxes of 'NO and superoxide ( • O 2 - ), for which model systems have been introduced. We here propose two new systems for nitros(yl)ation that avoid the shortcomings of previous models. Based on the thermal decomposition of 3-morpholinosydnonimine, equal fluxes of • NO and • O 2 - were generated and modulated by the …

Environmental Stressors and Their Impact on Health and Disease with Focus on Oxidative Stress

Epidemiological, preclinical and interventional clinical studies have demonstrated that environmental stressors are associated with health problems, namely cardiovascular diseases. According to estimations of the World Health Organization (WHO), environmental risk factors account for an appreciable part of global deaths and life years spent with disability. This Forum addresses the impact of the environmental risk factors such as traffic noise exposure, air pollution by particulate matter (PM), mental stress/loneliness, and the life style risk factor (water-pipe) smoking on health and disease with focus on the cardiovascular system. We will critically discuss the use of observatory/modifiab…

GLP-1 Analog Liraglutide Improves Vascular Function in Polymicrobial Sepsis by Reduction of Oxidative Stress and Inflammation

Sepsis causes high mortality in the setting of septic shock. LEADER and other trials revealed cardioprotective and anti-inflammatory properties of glucagon-like peptide-1 (GLP-1) analogs like liraglutide (Lira). We previously demonstrated improved survival in lipopolysaccharide (LPS)-induced endotoxemia by inhibition of GLP-1 degradation. Here we investigate the effects of Lira in the polymicrobial sepsis model of cecal ligation and puncture (CLP). C57BL/6J mice were intraperitoneally injected with Lira (200 µg/kg/d

Sirolimus-Induced Vascular Dysfunction

Objectives This study sought to analyze mechanisms that mediate vascular dysfunction induced by sirolimus. Background Despite excellent antirestenotic capacity, sirolimus-eluting stents have been found to trigger coronary endothelial dysfunction and impaired re-endothelialization. Methods To mimic the continuous sirolimus exposure of a stented vessel, Wistar rats underwent drug infusion with an osmotic pump for 7 days. Results Sirolimus treatment caused a marked degree of endothelial dysfunction as well as a desensitization of the vasculature to the endothelium-independent vasodilator nitroglycerin. Also, sirolimus stimulated intense transmural superoxide formation as detected by dihydroeth…

The Role of Mitochondrial Reactive Oxygen Species Formation for Age-Induced Vascular Dysfunction

Aging is an important risk factor for the development of cardiovascular diseases, which can be accelerated by atherosclerosis, diabetes, hypercholesterolemia, or obesity. Vascular aging is mainly characterized by endothelial dysfunction, an alteration of endothelium-dependent signaling processes, and vascular remodeling. The underlying mechanisms include increased production of reactive oxygen species (ROS), inactivation of nitric oxide (•NO), and subsequent formation of reactive nitrogen and oxygen species (RNOS). Elevated RNOS may exhibit new messenger functions by posttranslational oxidative modification of intracellular regulatory proteins or lead to irreversible alterations of biologic…

CD40/CD40L and Related Signaling Pathways in Cardiovascular Health and Disease—The Pros and Cons for Cardioprotection

The CD40–CD40 ligand (CD40L) dyad represents a scientific and clinical field that has raised many controversies in the past and cannot be clearly defined as being an either beneficial or harmful pathway. Being crucially involved in physiological immunological processes as well as pathological inflammatory reactions, the signaling pathway has been recognized as a key player in the development of both autoimmune and cardiovascular disease. Even though the possibilities of a therapeutic approach to the dyad were recognized decades ago, due to unfortunate events, detailed in this review, pharmacological treatment targeting the dyad, especially in patients suffering from atherosclerosis, is not …

Noise‐induced vascular dysfunction, oxidative stress and inflammationare improved by pharmacological heme oxygenase‐1 induction

NOX2ko Mice Show Largely Increased Expression of a Mutated NOX2 mRNA Encoding an Inactive NOX2 Protein

Background: The superoxide-generating enzyme nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2 or gp91phox, the phagocytic isoform) was reported as a major source of oxidative stress in various human diseases. Genetic deletion is widely used to study the impact of NOX2-derived reactive oxygen species (ROS) on disease development and progression in various animal models. Here, we investigate why NOX2 knockout mice show no NOX2 activity but express NOX2 mRNA and protein. Methods and Results: Oxidative burst (NOX2-dependent formation of ROS) was measured by L-012-based chemiluminescence and was largely absent in whole blood of NOX2 knockout mice. Protein expression was still de…

The roles of gut microbiota and circadian rhythm in the cardiovascular protective effects of polyphenols

Polyphenols are secondary metabolites of plants that have been widely studied for their health benefits as antioxidants. In the last decade, several clinical trials and epidemiological studies have shown that long-term consumption of polyphenol-rich diet protects against chronic diseases such as cancers and cardiovascular diseases. Current cardiovascular studies have also suggested an important role of gut microbiota and circadian rhythm in the pathogenesis metabolic and cardiovascular diseases. It is known that polyphenols can modulate the composition of core gut microbiota and interact with circadian clocks. In this article, we summarize recent findings, review the molecular mechanisms an…

Maternal Treatment of Spontaneously Hypertensive Rats With Pentaerythritol Tetranitrate Reduces Blood Pressure in Female Offspring

Pentaerythritol tetranitrate is devoid of nitrate tolerance and shows no reproductive or developmental toxicity in animal studies. Recently, pentaerythritol tetranitrate has been demonstrated to reduce the risk of intrauterine growth restriction and the risk of preterm birth in women with abnormal placental perfusion. This study was conducted to test the perinatal programming effect of pentaerythritol tetranitrate in spontaneously hypertensive rats, a rat model of genetic hypertension. Parental spontaneously hypertensive rats were treated with pentaerythritol tetranitrate (50 mg/kg per day) during pregnancy and lactation periods; the offspring received standard chow without pentaerythritol …

Resveratrol Reverses Endothelial Nitric-Oxide Synthase Uncoupling in Apolipoprotein E Knockout Mice

A crucial cause of the decreased bioactivity of nitric oxide (NO) in cardiovascular diseases is the uncoupling of the endothelial NO synthase (eNOS) caused by the oxidative stress-mediated deficiency of the NOS cofactor tetrahydrobiopterin (BH(4)). The reversal of eNOS uncoupling might represent a novel therapeutic approach. The treatment of apolipoprotein E knockout (ApoE-KO) mice with resveratrol resulted in the up-regulation of superoxide dismutase (SOD) isoforms (SOD1-SOD3), glutathione peroxidase 1 (GPx1), and catalase and the down-regulation of NADPH oxidases NOX2 and NOX4 in the hearts of ApoE-KO mice. This was associated with reductions in superoxide, 3-nitrotyrosine, and malondiald…

Vascular biotransformation of organic nitrates is independent of cytochrome P450 monooxygenases

Background and Purpose Organic nitrates such as nitroglycerin (NTG) or pentaerythritol tetranitrate (PETN) have been used for over a century in the treatment of angina or ischaemic heart disease. These compounds are prodrugs which release their nitrovasodilators upon enzymic bioactivation by aldehyde dehydrogenase (ALDH2) or cytochromes P450 (CYP). Whereas ALDH2 is known to directly activate organic nitrates in vessels, the contribution of vascular CYPs is unknown and was studied here. Experimental Approach As all CYPs depend on cytochrome P450 reductase (POR) as electron donor, we generated a smooth muscle cell-specific, inducible knockout mouse of POR (smcPOR−/−) to investigate the contri…

Mitochondrial Oxidative Stress, Mitochondrial DNA Damage and Their Role in Age-Related Vascular Dysfunction

The prevalence of cardiovascular diseases is significantly increased in the older population. Risk factors and predictors of future cardiovascular events such as hypertension, atherosclerosis, or diabetes are observed with higher frequency in elderly individuals. A major determinant of vascular aging is endothelial dysfunction, characterized by impaired endothelium-dependent signaling processes. Increased production of reactive oxygen species (ROS) leads to oxidative stress, loss of nitric oxide (•NO) signaling, loss of endothelial barrier function and infiltration of leukocytes to the vascular wall, explaining the low-grade inflammation characteristic for the aged vasculature. We here disc…

Mechanismen und klinischer Stellenwert der Nitrattoleranz. Diversität und Nebenwirkungen organischer Nitrate

Die wichtigste Beobachtung der letzten Jahre war, dass es sich bei den organischen Nitraten uberraschenderweise um eine heterogene Gruppe von Vasodilatantien handelt, denen gemeinsam ist, dass sie die losliche GC und die cGMP-abhangige Kinase aktivieren konnen. Alle klinisch wichtigen organischen Nitrate (GTN, ISDN und ISMN) auser dem PETN induzieren eine Toleranzentwicklung und eine endotheliale Dysfunktion bei chronischer Gabe. Aktuelle Arbeiten konnten insbesondere nach Gabe von GTN einen neuen Toleranz-Mechanismen identifizieren, der aus der Hemmung des Nitrat-bioaktivierenden Enzyms, der mitochondrialen Aldehyddehydrogenase (ALDH-2) sowie die Bildung reaktiver Sauerstoff- und Stickstof…

Time Response of Oxidative/Nitrosative Stress and Inflammation in LPS-Induced Endotoxaemia—A Comparative Study of Mice and Rats

Sepsis is a severe and multifactorial disease with a high mortality rate. It represents a strong inflammatory response to an infection and is associated with vascular inflammation and oxidative/nitrosative stress. Here, we studied the underlying time responses in the widely used lipopolysaccharide (LPS)-induced endotoxaemia model in mice and rats. LPS (10 mg/kg; from Salmonella Typhosa) was intraperitoneally injected into mice and rats. Animals of every species were divided into five groups and sacrificed at specific points in time (0, 3, 6, 9, 12 h). White blood cells (WBC) decreased significantly in both species after 3 h and partially recovered with time, whereas platelet decrease did no…

Molecular Mechanisms of the Crosstalk Between Mitochondrial and NADPH Oxidase Derived Reactive Oxygen Species in White Blood Cells - Implications for Cardiovascular Diseases

Protein tyrosine nitration and thiol oxidation by peroxynitrite-strategies to prevent these oxidative modifications.

The reaction product of nitric oxide and superoxide, peroxynitrite, is a potent biological oxidant. The most important oxidative protein modifications described for peroxynitrite are cysteine-thiol oxidation and tyrosine nitration. We have previously demonstrated that intrinsic heme-thiolate (P450)-dependent enzymatic catalysis increases the nitration of tyrosine 430 in prostacyclin synthase and results in loss of activity which contributes to endothelial dysfunction. We here report the sensitive peroxynitrite-dependent nitration of an over-expressed and partially purified human prostacyclin synthase (3.3 μM) with an EC50 value of 5 μM. Microsomal thiols in these preparations effectively co…

Organic Nitrate Therapy, Nitrate Tolerance, and Nitrate-Induced Endothelial Dysfunction: Emphasis on Redox Biology and Oxidative Stress

Abstract Organic nitrates, such as nitroglycerin (GTN), isosorbide-5-mononitrate and isosorbide dinitrate, and pentaerithrityl tetranitrate (PETN), when given acutely, have potent vasodilator effects improving symptoms in patients with acute and chronic congestive heart failure, stable coronary artery disease, acute coronary syndromes, or arterial hypertension. The mechanisms underlying vasodilation include the release of •NO or a related compound in response to intracellular bioactivation (for GTN, the mitochondrial aldehyde dehydrogenase [ALDH-2]) and activation of the enzyme, soluble guanylyl cyclase. Increasing cyclic guanosine-3′,-5′-monophosphate (cGMP) levels lead to an activation of…

Myeloperoxidase mediates neutrophil activation by association with CD11b/CD18 integrins.

Recruitment and activation of polymorphonuclear neutrophils (PMNs) reflects a primary immunological response to invading pathogens and has also emerged as a hallmark of vascular inflammation. One of the principal enzymes released upon PMN activation is myeloperoxidase (MPO), a heme protein that not only generates cytotoxic oxidants but also impacts deleteriously on nitric oxide-dependent signaling cascades within the vasculature. Because MPO also associates with the membrane of PMN, we evaluated whether MPO could also function as an autocrine modulator of PMN activation. The extent of PMN membrane-associated MPO was elevated in patients with acute inflammatory vascular disease compared with…

Environmental noise is a cardiovascular risk factor – mechanistic insights on oxidative stress, inflammatory pathways and endothelial dysfunction and preliminary data from diabetic mice.

Organic Nitrates and Nitrate Tolerance—State of the Art and Future Developments

The hemodynamic and antiischemic effects of nitroglycerin (GTN) are lost upon chronic administration due to the rapid development of nitrate tolerance. The mechanism of this phenomenon has puzzled several generations of scientists, but recent findings have led to novel hypotheses. The formation of reactive oxygen and nitrogen species in the mitochondria and the subsequent inhibition of the nitrate-bioactivating enzyme mitochondrial aldehyde dehydrogenase (ALDH-2) appear to play a central role, at least for GTN, that is, bioactivated by ALDH-2. Importantly, these findings provide the opportunity to reconcile the two “traditional” hypotheses of nitrate tolerance, that is, the one postulating …

Nitroglycerine causes mitochondrial reactive oxygen species production: In vitro mechanistic insights

Background Nitroglycerine (GTN) is an organic nitrate that has been used for more than 100 years. Despite its widespread clinical use, several aspects of the pharmacology of GTN remain elusive. In a recent study, the authors of the present study showed that GTN causes opening of the mitochondrial permeability transition pore (mPTP) and mitochondrial production of reactive oxygen species (ROS). Objective In the present study, it was tested whether GTN-induced ROS production depends on mitochondrial potassium ATP-dependent channel or mPTP opening, and/or GTN biotransformation. Methods and results Isolated rat heart mitochondria were incubated with succinate (a substrate for complex II) and GT…

Vascular Dysfunction and Oxidative Stress in Diabetic Rats - Comparison of Beneficial Effects of AT1- Receptor Blockade, Calcium Antagonist, or Combination Therapy

Native, Intact Glucagon-Like Peptide 1 Is a Natural Suppressor of Thrombus Growth Under Physiological Flow Conditions

Objective: In patients with diabetes mellitus, increased platelet reactivity predicts cardiac events. Limited evidence suggests that DPP-4 (dipeptidyl peptidase 4) influences platelets via GLP-1 (glucagon-like peptide 1)-dependent effects. Because DPP-4 inhibitors are frequently used in diabetes mellitus to improve the GLP-1-regulated glucose metabolism, we characterized the role of DPP-4 inhibition and of native intact versus DPP-4-cleaved GLP-1 on flow-dependent thrombus formation in mouse and human blood. Approach and Results: An ex vivo whole blood microfluidics model was applied to approach in vivo thrombosis and study collagen-dependent platelet adhesion, activation, and thrombus for…

Formation of 2-nitrophenol from salicylaldehyde as a suitable test for low peroxynitrite fluxes

There has been some dispute regarding reaction products formed at physiological peroxynitrite fluxes in the nanomolar range with phenolic molecules, when used to predict the behavior of protein-bound aromatic amino acids like tyrosine. Previous data showed that at nanomolar fluxes of peroxynitrite, nitration of these phenolic compounds was outcompeted by dimerization (e.g. biphenols or dityrosine). Using 3-morpholino sydnonimine (Sin-1), we created low fluxes of peroxynitrite in our reaction set-up to demonstrate that salicylaldehyde displays unique features in the detection of physiological fluxes of peroxynitrite, yielding detectable nitration but only minor dimerization products. By mean…

Cardiovascular disease burden from ambient air pollution in Europe reassessed using novel hazard ratio functions

Abstract Aims Ambient air pollution is a major health risk, leading to respiratory and cardiovascular mortality. A recent Global Exposure Mortality Model, based on an unmatched number of cohort studies in many countries, provides new hazard ratio functions, calling for re-evaluation of the disease burden. Accordingly, we estimated excess cardiovascular mortality attributed to air pollution in Europe. Methods and results The new hazard ratio functions have been combined with ambient air pollution exposure data to estimate the impacts in Europe and the 28 countries of the European Union (EU-28). The annual excess mortality rate from ambient air pollution in Europe is 790 000 [95% confidence i…

Hyperglycemia and oxidative stress in cultured endothelial cells – a comparison of primary endothelial cells with an immortalized endothelial cell line

Diabetes mellitus is a major risk factor for the development of cardiovascular disease and oxidative stress plays an important role in this process. Therefore, we investigated the effects of hyperglycemia on the formation of reactive oxygen species (ROS) and nitric oxide/cGMP signaling in two different endothelial cell cultures. Human umbilical vein endothelial cells (HUVEC) and EA.hy 926 cells showed increased oxidative stress and impaired NO-cGMP signaling in response to hyperglycemia. The major difference between the two different cell types was the dramatic decrease in viability in HUVEC whereas EA.hy cells showed rather increased growth under hyperglycemic conditions. Starvation led to…

Short-term e-cigarette vapour exposure causes vascular oxidative stress and dysfunction: evidence for a close connection to brain damage and a key role of the phagocytic NADPH oxidase (NOX-2)

Abstract Aims Electronic (e)-cigarettes have been marketed as a ‘healthy’ alternative to traditional combustible cigarettes and as an effective method of smoking cessation. There are, however, a paucity of data to support these claims. In fact, e-cigarettes are implicated in endothelial dysfunction and oxidative stress in the vasculature and the lungs. The mechanisms underlying these side effects remain unclear. Here, we investigated the effects of e-cigarette vapour on vascular function in smokers and experimental animals to determine the underlying mechanisms. Methods and results Acute e-cigarette smoking produced a marked impairment of endothelial function in chronic smokers determined b…

Germ-free housing conditions do not affect aortic root and aortic arch lesion size of late atherosclerotic low-density lipoprotein receptor-deficient mice

The microbiota has been linked to the development of atherosclerosis, but the functional impact of these resident bacteria on the lesion size and cellular composition of atherosclerotic plaques in the aorta has never been experimentally addressed with the germ-free low-density lipoprotein receptor-deficient (Ldlr(-/-)) mouse atherosclerosis model. Here, we report that 16 weeks of high-fat diet (HFD) feeding of hypercholesterolemicLdlr(-/-)mice at germ-free (GF) housing conditions did not impact relative aortic root plaque size, macrophage content, and necrotic core area. Likewise, we did not find changes in the relative aortic arch lesion size. However, late atherosclerotic GFLdlr(-/-)mice …

Characterization of New Organic Nitrate Hybrid Drugs Covalently Bound to Valsartan and Cilostazol

Background and Purpose: Organic nitrates represent a group of nitrovasodilators that are clinically used for the treatment of ischemic heart disease. With the present studies we synthesized and characterized new organic nitrate hybrid molecules. Compounds CLC-1265 (valsartan mononitrate) and CLC-1280 (valsartan dinitrate) are derivatives of the angiotensin receptor blocker valsartan, with CLC-1265 containing a single organic nitrate linker and CLC-1280 also containing a second, different linker. Compounds CLC-2000 (cilostazol mononitrate) and CLC-2100 (cilostazol dinitrate) are nitrate derivatives of the phosphodiesterase III inhibitor cilostazol. All compounds are designed as hybrid molecu…

Reconstitution of Myelomonocyte-Depleted Mice With Monocytes, But Not With Neutrophils, Reestablishes Arterial Hypertension and Oxidative Stress in Response To Angiogtensin II

Effect of soluble guanylyl cyclase activator and stimulator therapy on nitroglycerin-induced nitrate tolerance in rats

Chronic nitroglycerin (GTN) anti-ischemic therapy induces side effects such as nitrate tolerance and endothelial dysfunction. Both phenomena could be based on a desensitization/oxidation of the soluble guanylyl cyclase (sGC). Therefore, the present study aims at investigating the effects of the therapy with the sGC activator BAY 60-2770 and the sGC stimulator BAY 41-8543 on side effects induced by chronic nitroglycerin treatment. Male Wistar rats were treated with nitroglycerin (100mg/kg/d for 3.5days, s.c. in ethanol) and BAY 60-2770 (0.5 or 2.5mg/kg/d) or BAY 41-8543 (1 and 5mg/kg/d) for 6days. Therapy with BAY 60-2770 but not with BAY 41-8543 improved nitroglycerin-triggered endothelial …

Redox Regulation of Dihydrofolate Reductase: Friend or Troublemaker?

Oxidative stress is a hallmark of cardiovascular diseases1 and a major contributor to vascular dysfunction.2 On the basis on recent concepts, vascular oxidative stress is caused mainly by infiltrating inflammatory cells such as monocytes/macrophages or leucocytes,3,4 producing so-called kindling radicals that lead to the activation of secondary, vascular enzymatic sources of reactive oxygen species (mainly superoxide).2,5 A prominent example is the uncoupled nitric oxide (NO) synthase, which means that an NO-producing antiatherosclerotic enzyme is getting switched to a superoxide-producing proatherosclerotic enzyme.2 Molecular mechanisms causing endothelial NO synthase (eNOS) uncoupling or …

Uncoupling of Endothelial Nitric Oxide Synthase in Perivascular Adipose Tissue of Diet-Induced Obese Mice

Objective— The present study was conducted to investigate the contribution of perivascular adipose tissue (PVAT) to vascular dysfunction in a mouse model of diet-induced obesity. Approach and Results— Obesity was induced in male C57BL/6J mice with a high-fat diet for 20 weeks, and vascular function was studied with myograph. In PVAT-free aortas isolated from obese mice, the endothelium-dependent, nitric oxide–mediated vasodilator response to acetylcholine remained normal. In contrast, a clear reduction in the vasodilator response to acetylcholine was observed in aortas from obese mice when PVAT was left in place. Adipocytes in PVAT were clearly positive in endothelial nitric oxide synthase…

the role of mitochondrial aldehyde dehydrognase (ALDH-2) for bioactivation of organic nitrates: “Proof of concept” through investigations in ALDH-2 knockout mice

Pathophysiological role of oxidative stress in systolic and diastolic heart failure and its therapeutic implications

Abstract Systolic and diastolic myocardial dysfunction has been demonstrated to be associated with an activation of the circulating and local renin–angiotensin–aldosterone system (RAAS), and with a subsequent inappropriately increased production of reactive oxygen species (ROS). While, at low concentrations, ROS modulate important physiological functions through changes in cellular signalling and gene expression, overproduction of ROS may adversely alter cardiac mechanics, leading to further worsening of systolic and diastolic function. In addition, vascular endothelial dysfunction due to uncoupling of the nitric oxide synthase, activation of vascular and phagocytic membrane oxidases or mit…

Cigarette Smoking Is Related to Endothelial Dysfunction of Resistance, but Not Conduit Arteries in the General Population—Results From the Gutenberg Health Study

Aims: Cigarette smoking is one of the most complex and least understood cardiovascular risk factors. Importantly, differences in the tobacco-related pathophysiology of endothelial dysfunction, an early event in atherogenesis, between circulatory beds remain elusive. Therefore, this study evaluated how smoking impacts endothelial function of conduit and resistance arteries in a large population-based cohort.Methods and results: 15,010 participants (aged 35–74 years) of the Gutenberg Health Study were examined at baseline from 2007 to 2012. Smoking status, pack-years of smoking, and years since quitting smoking were assessed by a computer-assisted interview. Endothelial function of conduit an…

Free radical biology of the cardiovascular system

Most cardiovascular diseases (CVDs), as well as age-related cardiovascular alterations, are accompanied by increases in oxidative stress, usually due to increased generation and/or decreased metabolism of ROS (reactive oxygen species; for example superoxide radicals) and RNS (reactive nitrogen species; for example peroxynitrite). The superoxide anion is generated by several enzymatic reactions, including a variety of NADPH oxidases and uncoupled eNOS (endothelial NO synthase). To relieve the burden caused by this generation of free radicals, which also occurs as part of normal physiological processes, such as mitochondrial respiratory chain activity, mammalian systems have developed endogen…

Effects of gaseous and solid constituents of air pollution on endothelial function

Abstract Ambient air pollution is a leading cause of non-communicable disease globally. The largest proportion of deaths and morbidity due to air pollution is now known to be due to cardiovascular disorders. Several particulate and gaseous air pollutants can trigger acute events (e.g. myocardial infarction, stroke, heart failure). While the mechanisms by which air pollutants cause cardiovascular events is undergoing continual refinement, the preponderant evidence support rapid effects of a diversity of pollutants including all particulate pollutants (e.g. course, fine, ultrafine particles) and gaseous pollutants such as ozone, on vascular function. Indeed alterations in endothelial function…

Nitrate tolerance as a model of vascular dysfunction: Roles for mitochondrial aldehyde dehydrogenase and mitochondrial oxidative stress

Organic nitrates are a group of very effective anti-ischemic drugs. They are used for the treatment of patients with stable angina, acute myocardial infarction and chronic congestive heart failure. A major therapeutic limitation inherent to organic nitrates is the development of tolerance, which occurs during chronic treatment with these agents. The mechanisms underlying nitrate tolerance remain incompletely defined and are likely multifactorial. One mechanism seems to be a diminished bioconversion of nitroglycerin, another seems to be the induction of vascular oxidative stress, and a third may include neurohumoral adaptations. Recent studies have revealed that mitochondrial reactive oxygen…

Heme oxygenase-1: a novel key player in the development of tolerance in response to organic nitrates.

Objective— Nitrate tolerance is likely attributable to an increased production of reactive oxygen species (ROS) leading to an inhibition of the mitochondrial aldehyde dehydrogenase (ALDH-2), representing the nitroglycerin (GTN) and pentaerythrityl tetranitrate (PETN) bioactivating enzyme, and to impaired nitric oxide bioactivity and signaling. We tested whether differences in their capacity to induce heme oxygenase-1 (HO-1) might explain why PETN and not GTN therapy is devoid of nitrate and cross-tolerance. Methods and Results— Wistar rats were treated with PETN or GTN (10.5 or 6.6 μg/kg/min for 4 days). In contrast to GTN, PETN did not induce nitrate tolerance or cross-tolerance as assess…

Tolerance to nitroglycerin-induced preconditioning of the endothelium: a human in vivo study

Damage and dysfunction of the vascular endothelium critically influence clinical outcomes after ischemia and reperfusion (I/R). Brief exposure to organic nitrates can protect the vascular endothelium from I/R injury via a mechanism that is similar to ischemic preconditioning and is independent of hemodynamic changes. The clinical relevance of these protective effects clearly depends on whether they can be sustained over time. Twenty-four healthy (age 25–32) male volunteers were randomized to receive 1) transdermal nitroglycerin (GTN; 0.6 mg/h) administered for 2 h on 1 day only, 2) transdermal GTN for 2 h/day for 7 days, or 3) continuous therapy with transdermal GTN for 7 days. Eight volunt…

Do We Still Need Organic Nitrates?⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.

Organic nitrates are still quite frequently used for the treatment of acute and chronic angina, and acute and chronic congestive heart failure. When given acutely, their effectiveness is undisputable; however, their long-term efficacy is substantially limited due to the development of tolerance ([1

Environmental Factors Such as Noise and Air Pollution and Vascular Disease

Significance: According to the World Health Organization, noncommunicable diseases are the globally leading cause of mortality. Recent Advances: About 71% of 56 million deaths that occurred worldwide are due to noncommunicable cardiovascular risk factors, including tobacco smoking, unhealthy diets, lack of physical activity, overweight, arterial hypertension, diabetes, and hypercholesterolemia, which can be either avoided or substantially reduced. Critical Issues: Thus, it is estimated that 80% of premature heart disease, stroke, and diabetes can be prevented. More recent evidence indicates that environmental stressors such as noise and air pollution contribute significantly to the global b…

NECAB2 participates in an endosomal pathway of mitochondrial stress response at striatal synapses

Synaptic signaling depends on ATP generated by mitochondria. Due to extensive connectivity, the striatum is especially vulnerable to mitochondrial dysfunction and thus requires efficient mitochondrial quality control. We found that the neuronal calcium-binding protein NECAB2 ensures synaptic function in the striatum by increasing mitochondrial efficiency. NECAB2 associates with early endosomes and mitochondria at striatal synapses. Loss of NECAB2 dysregulates proteins of the endosomal ESCRT machinery and oxidative phosphorylation. Mitochondria from NECAB2-deficient mice are more abundant but less efficient. These mitochondria exhibit increased respiration and superoxide production but produ…

Phenotypic characterisation of pro-inflammatory monocytes and dendritic cells in peripheral arterial disease

SummaryAtherosclerosis is a chronic inflammatory process involving antigen-presenting cells like monocytes and dendritic cells (DC). The aim of this study was to perform a phenotypic characterisation of these cell types in patients with different degrees of peripheral arterial disease (PAD). Sixty patients with PAD [N= 30 intermittent claudication (IC), N= 30 critical limb ischemia (CLI)] and 30 controls were included. Peripheral blood leucocytes were analysed from peripheral blood by flow cytometry using different gating strategies to directly identify and analyse monocytes, myeloid DC, (mDC) and plasmacytoid DC (pDC). PAD patients showed a significantly higher proportion of proinflammator…

Heterozygous deficiency of manganese superoxide dismutase in mice (Mn-SOD+/-): a novel approach to assess the role of oxidative stress for the development of nitrate tolerance.

Nitroglycerin (GTN)-induced tolerance was reported to be associated with increased levels of reactive oxygen species (ROS) in mitochondria. In the present study, we further investigated the role of ROS for the development of nitrate tolerance by using heterozygous manganese superoxide dismutase knock-out mice (Mn-SOD+/-). Mn-SOD is acknowledged as a major sink for mitochondrial superoxide. Vasodilator potency of mouse aorta in response to acetylcholine and GTN was assessed by isometric tension studies. Mitochondrial ROS formation was detected by 8-amino-5-chloro-7-phenylpyrido[3,4-d]pyridazine-1,4-(2H,3H)dione sodium salt (L-012)-enhanced chemiluminescence and mitochondrial aldehyde dehydro…

Endothelial GLP-1 (Glucagon-Like Peptide 1) Receptor Mediates Cardiovascular Protection by Liraglutide In Mice With Experimental Arterial Hypertension

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Glucose-independent improvement of vascular dysfunction in experimental sepsis by dipeptidyl-peptidase 4 inhibition.

Aims Dipeptidyl peptidase-4 (DPP-4) inhibitors are a novel class of drugs for the treatment of hyperglycaemia. Preliminary evidence suggests that their antioxidant and anti-inflammatory effects may have beneficial effects on the cardiovascular complications of diabetes. In the present study, we investigate in an experimental sepsis model whether linagliptin exerts pleiotropic vascular effects independent of its glucose-lowering properties. Methods and results Linagliptin (83 mg/kg chow for 7days) was administered in a rat model of lipopolysaccharide (LPS) (10 mg/kg, single i.p. dose/24 h)-induced sepsis. Vascular relaxation, reactive oxygen species (ROS) formation, expression of NADPH oxida…

ALDH-2 deficiency increases cardiovascular oxidative stress--evidence for indirect antioxidative properties.

Abstract Mitochondrial aldehyde dehydrogenase (ALDH-2) reduces reactive oxygen species (ROS) formation related to toxic aldehydes; additionally, it provides a bioactivating pathway for nitroglycerin. Since acetaldehyde, nitroglycerin, and doxorubicin treatment provoke mitochondrial oxidative stress, we used ALDH-2−/− mice and purified recombinant human ALDH-2 to test the hypothesis that ALDH-2 has an indirect antioxidant function in mitochondria. Antioxidant capacity of purified ALDH-2 was comparable to equimolar doses of glutathione, cysteine, and dithiothreitol; mitochondrial oxidative stress was comparable in C57Bl6 and ALDH-2−/− mice after acute challenges with nitroglycerin or doxorubi…

Mechanisms of Increased Vascular Superoxide Production in an Experimental Model of Idiopathic Dilated Cardiomyopathy

Objective— In the present study, we sought to identify mechanisms underlying increased oxidative stress in vascular tissue in an experimental animal model of chronic congestive heart failure (CHF). Methods and Results— Superoxide and nitric oxide (NO) was measured in vessels from cardiomyopathic hamsters (CHF hamsters) and golden Syrian hamsters. We also determined expression of endothelial nitric oxide synthase (NOSIII), the soluble guanylyl cyclase, the cGMP-dependent kinase, and the NADPH oxidase. To analyze the contribution of the renin-angiotensin system to oxidative stress, CHF hamsters were treated with the angiotensin-converting enzyme inhibitor captopril for 200 days (120 mg · kg …

Mitochondrial aldehyde dehydrogenase (ALDH-2)--maker of and marker for nitrate tolerance in response to nitroglycerin treatment.

The hemodynamic and anti-ischemic effects of nitroglycerin (GTN) are rapidly blunted as a result of the development of nitrate tolerance. Long-term nitrate treatment also is associated with decreased vascular responsiveness caused by changes in intrinsic mechanisms of the tolerant vasculature itself. According to the oxidative stress concept, increased vascular superoxide and peroxynitrite production as well as an increased sensitivity to vasoconstrictors secondary to activation of protein kinase C as well as vascular NADPH oxidases contribute to the development of tolerance. Recent experimental work has defined new tolerance mechanisms, including inhibition of the enzyme that bioactivates …

Ambient Air Pollution Increases the Risk of Cerebrovascular and Neuropsychiatric Disorders through Induction of Inflammation and Oxidative Stress

Exposure to ambient air pollution is a well-established determinant of health and disease. The Lancet Commission on pollution and health concludes that air pollution is the leading environmental cause of global disease and premature death. Indeed, there is a growing body of evidence that links air pollution not only to adverse cardiorespiratory effects but also to increased risk of cerebrovascular and neuropsychiatric disorders. Despite being a relatively new area of investigation, overall, there is mounting recent evidence showing that exposure to multiple air pollutants, in particular to fine particles, may affect the central nervous system (CNS) and brain health, thereby contributing to …

The "exposome" concept - how environmental risk factors influence cardiovascular health.

There is general consensus that environmental pollution and non-chemical stressors contribute to the incidence and prevalence of chronic noncommunicable disease (e.g. cardiovascular, metabolic and mental). Clinical and epidemiological studies support that air pollution and traffic noise are associated with a higher risk for cardiovascular disease and significantly contribute to overall mortality. In this respect, the “exposome” provides a comprehensive description of lifelong exposure history. A recent publication using an updated global exposure-mortality model found that the global all-cause mortality rate attributable to ambient air pollution by PM2.5 and O3 was 8.79 (95% CI 7.11–10.41) …

Redox signaling (cross-talk) from and to mitochondria involves mitochondrial pores and reactive oxygen species

This review highlights the important role of redox signaling between mitochondria and NADPH oxidases. Besides the definition and general importance of redox signaling, the cross-talk between mitochondrial and Nox-derived reactive oxygen species (ROS) is discussed on the basis of 4 different examples. In the first model, angiotensin-II is discussed as a trigger for NADPH oxidase activation with subsequent ROS-dependent opening of mitochondrial ATP-sensitive potassium channels leading to depolarization of mitochondrial membrane potential followed by mitochondrial ROS formation and respiratory dysfunction. This concept was supported by observations that ethidium bromide-induced mitochondrial d…

Role of Reduced Lipoic Acid in the Redox Regulation of Mitochondrial Aldehyde Dehydrogenase (ALDH-2) Activity

Chronic therapy with nitroglycerin results in a rapid development of nitrate tolerance, which is associated with an increased production of reactive oxygen species. We have recently shown that mitochondria are an important source of nitroglycerin-induced oxidants and that the nitroglycerin-bioactivating mitochondrial aldehyde dehydrogenase is oxidatively inactivated in the setting of tolerance. Here we investigated the effect of various oxidants on aldehyde dehydrogenase activity and its restoration by dihydrolipoic acid. In vivo tolerance in Wistar rats was induced by infusion of nitroglycerin (6.6 microg/kg/min, 4 days). Vascular reactivity was measured by isometric tension studies of iso…

NADPH Oxidase Accounts for Enhanced Superoxide Production and Impaired Endothelium-Dependent Smooth Muscle Relaxation in BKβ1 −/− Mice

Objective— Nitric oxide (NO)-induced vasorelaxation involves activation of large conductance Ca 2+ -activated K + channels (BK). A regulatory BKβ1 subunit confers Ca 2+ , voltage, and NO/cGMP sensitivity to the BK channel. We investigated whether endothelial function and NO/cGMP signaling is affected by a deletion of the β1-subunit. Methods and Results— Vascular superoxide in BKβ1 −/− was measured using the fluorescent dye hydroethidine and lucigenin-enhanced chemiluminescence. Vascular NO formation was analyzed using electron paramagnetic resonance (EPR), expression of NADPH oxidase subunits, the endothelial NO synthase (eNOS), the soluble guanylyl cyclase (sGC), as well as the activity a…

Sodium-glucose cotransporter 2 inhibitors, diabetes, and oxidative stress

Abstract Diabetes and related metabolic diseases have a high prevalence with increasing incidence and create a significant socioeconomic burden by their contribution to global mortality and disability adjusted life years. Whereas the contribution of communicable disease to global deaths decreased during the last 25 years, the contribution by chronic noncommunicable disease and environmental factors increased within this time period. According to data of the Global Burden of Disease Study high fasting plasma glucose and high total cholesterol rank in place 3 and 4 in the list of global health risk factors, just behind high blood pressure and smoking. Diabetes adversely affects endothelial an…

Critical limb ischaemia is characterised by an increased production of whole blood reactive oxygen species and expression of TREM-1 on neutrophils

Atherosclerosis is a chronic inflammatory process involving polymorphonuclear neutrophils (PMN) and formation of reactive oxygen species (ROS). The aim of the present study was to investigate the phenotype of inflammatory cells in regard to the expression of triggering receptor expressed on myeloid cells (TREM)-1 and its soluble form (sTREM-1) as well as its relationship with oxidative stress in peripheral artery disease (PAD) patients.In total 90 patients with PAD (N = 30 intermittent claudication (IC)300 m absolute walking distance, N = 30 IC300 m absolute walking distance, N = 30 critical limb ischaemia (CLI)) and 30 control persons were included. ROS formation was measured at basal or s…

Deficiency of glutathione peroxidase-1 accelerates the progression of atherosclerosis in apolipoprotein E-deficient mice.

Background— We have recently demonstrated that activity of red blood cell glutathione peroxidase-1 is inversely associated with the risk of cardiovascular events in patients with coronary artery disease. The present study analyzed the effect of glutathione peroxidase-1 deficiency on atherogenesis in the apolipoprotein E-deficient mouse. Methods and Results— Female apolipoprotein E-deficient mice with and without glutathione peroxidase-1 deficiency were placed on a Western-type diet for another 6, 12, or 24 weeks. After 24 weeks on Western-type diet, double-knockout mice (GPx-1 −/− ApoE −/− ) developed significantly more atherosclerosis than control apolipoprotein E-deficient mice. Moreover…

Crosstalk of mitochondria with NADPH oxidase via reactive oxygen and nitrogen species signalling and its role for vascular function

Cardiovascular diseases are associated with and/or caused by oxidative stress. This concept has been proven by using the approach of genetic deletion of reactive species producing (pro-oxidant) enzymes as well as by the overexpression of reactive species detoxifying (antioxidant) enzymes leading to a marked reduction of reactive oxygen and nitrogen species (RONS) and in parallel to an amelioration of the severity of diseases. Likewise, the development and progression of cardiovascular diseases is aggravated by overexpression of RONS producing enzymes as well as deletion of antioxidant RONS detoxifying enzymes. Thus, the consequences of the interaction (redox crosstalk) of superoxide/hydroge…

Environmental aircraft noise aggravates oxidative DNA damage, granulocyte oxidative burst and nitrate resistance inOgg1–/–mice

Background: Large epidemiological studies point towards a link between the incidence of arterial hypertension, ischaemic heart disease, metabolic disease and exposure to traffic noise, supporting t...

Physical Activity in Polluted Air—Net Benefit or Harm to Cardiovascular Health? A Comprehensive Review

Both exposure to higher levels of polluted air and physical inactivity are crucial risk factors for the development and progression of major noncommunicable diseases and, in particular, of cardiovascular disease. In this context, the World Health Organization estimated 4.2 and 3.2 million global deaths per year in response to ambient air pollution and insufficient physical activity, respectively. While regular physical activity is well known to improve general health, it may also increase the uptake and deposit of air pollutants in the lungs/airways and circulation, due to increased breathing frequency and minute ventilation, thus increasing the risk of cardiovascular disease. Thus, determi…

Smoking and Neuropsychiatric Disease-Associations and Underlying Mechanisms.

Despite extensive efforts to combat cigarette smoking/tobacco use, it still remains a leading cause of global morbidity and mortality, killing more than eight million people each year. While tobacco smoking is a major risk factor for non-communicable diseases related to the four main groups—cardiovascular disease, cancer, chronic lung disease, and diabetes—its impact on neuropsychiatric risk is rather elusive. The aim of this review article is to emphasize the importance of smoking as a potential risk factor for neuropsychiatric disease and to identify central pathophysiological mechanisms that may contribute to this relationship. There is strong evidence from epidemiological and experiment…

Characterization of the Antioxidant Properties of Pentaerithrityl Tetranitrate (PETN)-Induction of the Intrinsic Antioxidative System Heme Oxygenase-1 (HO-1)

Organic nitrates are among the oldest and yet most commonly employed drugs in the chronic therapy of coronary artery disease and congestive heart failure. While they have long been used in clinical practise, our understanding of their mechanism of action and of their side effects remains incomplete. To date, the most commonly employed nitrates are isosorbide mononitrate (ISMN), isosorbide dinitrate (ISDN), and nitroglycerin (GTN). Another nitrate, pentaerithrityl tetranitrate (PETN), has long been employed in eastern European countries and is currently being reintroduced also in western countries. So far, PETN is the only organic nitrate in clinical use, which is devoid of induction of oxid…

The Adverse Effects of Environmental Noise Exposure on Oxidative Stress and Cardiovascular Risk

Abstract Epidemiological studies have provided evidence that traffic noise exposure is linked to cardiovascular diseases such as arterial hypertension, myocardial infarction, and stroke. Noise is a nonspecific stressor that activates the autonomous nervous system and endocrine signaling. According to the noise reaction model introduced by Babisch and colleagues, chronic low levels of noise can cause so-called nonauditory effects, such as disturbances of activity, sleep, and communication, which can trigger a number of emotional responses, including annoyance and subsequent stress. Chronic stress in turn is associated with cardiovascular risk factors, comprising increased blood pressure and …

The role of mitochondrial reactive oxygen species, NO and H2S in ischaemia/reperfusion injury and cardioprotection

Redox signalling in mitochondria plays an important role in myocardial ischaemia/reperfusion (I/R) injury and in cardioprotection. Reactive oxygen and nitrogen species (ROS/RNS) modify cellular structures and functions by means of covalent changes in proteins including among others S‐nitros(yl)ation by nitric oxide (NO) and its derivatives, and S‐sulphydration by hydrogen sulphide (H2S). Many enzymes are involved in the mitochondrial formation and handling of ROS, NO and H2S under physiological and pathological conditions. In particular, the balance between formation and removal of reactive species is impaired during I/R favouring their accumulation. Therefore, various interventions aimed a…

CD40L controls obesity-associated vascular inflammation, oxidative stress, and endothelial dysfunction in high fat diet-treated and db/db mice

Abstract Aims CD40 ligand (CD40L) signaling controls vascular oxidative stress and related dysfunction in angiotensin-II-induced arterial hypertension by regulating vascular immune cell recruitment and platelet activation. Here we investigated the role of CD40L in experimental hyperlipidemia. Methods and results Male wild type and CD40L−/− mice (C57BL/6 background) were subjected to high fat diet for sixteen weeks. Weight, cholesterol, HDL, and LDL levels, endothelial function (isometric tension recording), oxidative stress (NADPH oxidase expression, dihydroethidium fluorescence) and inflammatory parameters (inducible nitric oxide synthase, interleukin-6 expression) were assessed. CD40L exp…

Nitrate Reductase Activity of Mitochondrial Aldehyde Dehydrogenase (ALDH-2) as a Redox Sensor for Cardiovascular Oxidative Stress

In 2002, mitochondrial aldehyde dehydrogenase (ALDH-2) was identified as an organic nitrate bioactivating enzyme. This so-called nitrate reductase activity denitrates nitroglycerin (glycerol trinitrate) to its 1,2-glycerol dinitrate metabolite and nitrite. This reaction relies on reduced thiols at the active site of the enzyme and on the presence of reduced dithiols as the electron source. During bioconversion of nitroglycerin, and also in the presence of reactive oxygen and nitrogen species, the active site thiols of ALDH-2 are oxidized and the enzyme looses its activity. We, therefore, speculated that ALDH-2 activity could be a useful marker for cardiovascular oxidative stress. Indeed, th…

Environmental risk factors and cardiovascular diseases: a comprehensive expert review.

Abstract Non-communicable diseases (NCDs) are fatal for more than 38 million people each year and are thus the main contributors to the global burden of disease accounting for 70% of mortality. The majority of these deaths are caused by cardiovascular disease (CVD). The risk of NCDs is strongly associated with exposure to environmental stressors such as pollutants in the air, noise exposure, artificial light at night, and climate change, including heat extremes, desert storms, and wildfires. In addition to the traditional risk factors for CVD such as diabetes, arterial hypertension, smoking, hypercholesterolaemia, and genetic predisposition, there is a growing body of evidence showing that …

The anti-cancer drug doxorubicin induces substantial epigenetic changes in cultured cardiomyocytes.

Abstract The anthracycline doxorubicin (DOX) is widely used in cancer therapy with the limitation of cardiotoxicity leading to the development of congestive heart failure. DOX-induced oxidative stress and changes of the phosphoproteome as well as epigenome were described but the exact mechanisms of the adverse long-term effects are still elusive. Here, we tested the impact of DOX treatment on cell death, oxidative stress parameters and expression profiles of proteins involved in epigenetic pathways in a cardiomyocyte cell culture model. Markers of oxidative stress, apoptosis and expression of proteins involved in epigenetic processes were assessed by immunoblotting in cultured rat myoblasts…

Reduction of environmental pollutants for prevention of cardiovascular disease: it’s time to act

Abstract

Inorganic nitrite and nitrate in cardiovascular therapy: A better alternative to organic nitrates as nitric oxide donors?

In 1867 the organic nitrite, amyl nitrite, was introduced as a therapeutic agent in the treatment of angina pectoris and was later substituted by the organic nitrate nitroglycerin (NTG). Despite having a highly potent vasodilator capacity in veins>coronary arteries>arterioles, the vasodilator effects NTG are rapidly attenuated by the development of nitrate tolerance. We and others established that NTG treatment stimulates the production of reactive oxygen species such as superoxide and peroxynitrite with subsequent marked attenuation of the NTG vasodilator potency. The nitrite anion (NO2-) has more recently been characterized to possess novel pharmacotherapeutic actions such as modulation o…

Glucagon-like peptide-1 (GLP-1) receptor agonists and their cardiovascular benefits-The role of the GLP-1 receptor.

Cardiovascular outcome trials revealed cardiovascular benefits for type 2 diabetes mellitus patients when treated with long-acting glucagon-like peptide-1 (GLP-1) receptor agonists. In the last decade, major advances were made characterising the physiological effects of GLP-1 and its action on numerous targets including brain, liver, kidney, heart and blood vessels. However, the effects of GLP-1 and receptor agonists, and the GLP-1 receptor on the cardiovascular system have not been fully elucidated. We compare results from cardiovascular outcome trials of GLP-1 receptor agonists and review pleiotropic clinical and preclinical data concerning cardiovascular protection beyond glycaemic contr…

Environmental Noise and the Cardiovascular System

Abstract Noise has been found associated with annoyance, stress, sleep disturbance, and impaired cognitive performance. Furthermore, epidemiological studies have found that environmental noise is associated with an increased incidence of arterial hypertension, myocardial infarction, heart failure, and stroke. Observational and translational studies indicate that especially nighttime noise increases levels of stress hormones and vascular oxidative stress, which may lead to endothelial dysfunction and arterial hypertension. Novel experimental studies found aircraft noise to be associated with oxidative stress–induced vascular damage, mediated by activation of the NADPH oxidase, uncoupling of …

Gliptins Suppress Inflammatory Macrophage Activation to Mitigate Inflammation, Fibrosis, Oxidative Stress, and Vascular Dysfunction in Models of Nonalcoholic Steatohepatitis and Liver Fibrosis

Abstract Aims: Nonalcoholic steatohepatitis (NASH) is characterized by steatosis, panlobular inflammation, liver fibrosis, and increased cardiovascular mortality. Dipeptidyl peptidase-4 inhibitors (gliptins) are indirect glucagon-like peptide 1 agonists with antidiabetic and anti-inflammatory activity, used for the treatment of type 2 diabetes. Their potential and underlying mechanisms to treat metabolic liver inflammation and fibrosis as well as the associated vascular dysfunction remain to be explored. Results: In the methionine/choline-deficient (MCD) diet and Mdr2−/− models of NASH and liver fibrosis, treatment with sitagliptin and linagliptin significantly decreased parameters of steat…

Abstract 412: The Sodium-Glucose Cotransporter 2 Inhibitor Empagliflozin Improves Diabetic Complications in the Streptozotocin Type 1 Diabetes Mellitus Model by Interfering With Glucotoxicity and Rescue of Beta-Cell Function

Objectives: In diabetes, cardiovascular complications are associated with endothelial dysfunction and oxidative stress. Empagliflozin (Empa), as a selective sodium-glucose co-transporter 2 inhibitor (SGLT2i) in clinical development, offers a promising novel approach for the treatment of type 2 diabetes by enhancing urinary glucose excretion. The aim of the present study was to test whether treatment with Empa could improve endothelial dysfunction in type I diabetic rats via reduction of glucotoxicity and associated oxidative stress. Research Design and Methods: Type I diabetes in Wistar rats was induced by an intravenous injection of streptozotocin (60 mg/kg). One week after injection Empa…

Effects of noise on vascular function, oxidative stress, and inflammation: mechanistic insight from studies in mice

Aims Epidemiological studies indicate that traffic noise increases the incidence of coronary artery disease, hypertension and stroke. The underlying mechanisms remain largely unknown. Field studies with nighttime noise exposure demonstrate that aircraft noise leads to vascular dysfunction, which is markedly improved by vitamin C, suggesting a key role of oxidative stress in causing this phenomenon. Methods and results We developed a novel animal model to study the vascular consequences of aircraft noise exposure. Peak sound levels of 85 and mean sound level of 72 dBA applied by loudspeakers for 4 days caused an increase in systolic blood pressure, plasma noradrenaline and angiotensin II lev…

Mitochondrial redox signaling: Interaction of mitochondrial reactive oxygen species with other sources of oxidative stress.

Significance: Oxidative stress is a well established hallmark of cardiovascular disease and there is strong evidence for a causal role of reactive oxygen and nitrogen species (RONS) therein. Recent Advances: Improvement of cardiovascular complications by genetic deletion of RONS producing enzymes and overexpression of RONS degrading enzymes proved the involvement of these species in cardiovascular disease at a molecular level. Vice versa, overexpression of RONS producing enzymes as well as deletion of antioxidant enzymes was demonstrated to aggravate cardiovascular complications. Critical Issues: With the present overview we present and discuss different pathways how mitochondrial RONS inte…

Angiotensin II-induced vascular dysfunction depends on interferon-γ-driven immune cell recruitment and mutual activation of monocytes and NK-cells.

Objective— Immune cells contribute to angiotensin II (ATII)–induced vascular dysfunction and inflammation. Interferon-γ (IFN-γ), an inflammatory cytokine exclusively produced by immune cells, seems to be involved in ATII-driven cardiovascular injury, but the actions and cellular source of IFN-γ remain incompletely understood. Approach and Results— IFN-γ −/− and Tbx21 −/− mice were partially protected from ATII-induced (1 mg/kg per day of ATII, infused subcutaneously by miniosmotic pumps) vascular endothelial and smooth muscle dysfunction, whereas mice overexpressing IFN-γ showed constitutive vascular dysfunction. Absence of T-box expressed in T cells (T-bet), the IFN-γ transcription factor…

First Evidence for a Crosstalk Between Mitochondrial and NADPH Oxidase-Derived Reactive Oxygen Species in Nitroglycerin-Triggered Vascular Dysfunction

Chronic nitroglycerin treatment results in development of nitrate tolerance associated with endothelial dysfunction (ED). We sought to clarify how mitochondria- and NADPH oxidase (Nox)-derived reactive oxygen species (ROS) contribute to nitrate tolerance and nitroglycerin-induced ED. Nitrate tolerance was induced by nitroglycerin infusion in male Wistar rats (100 microg/h/4 day) and in C57/Bl6, p47(phox/) and gp91(phox/) mice (50 microg/h/4 day). Protein and mRNA expression of Nox subunits were unaltered by chronic nitroglycerin treatment. Oxidative stress was determined in vascular rings and mitochondrial fractions of nitroglycerin-treated animals by L-012 enhanced chemiluminescence, revea…

Regulation of Human ALDH-2 Activity by Electrophiles – Implications for Organic Nitrate Induced Tolerance, Oxidative Stress and Reactive Fatty Acid Metabolites in MI

New and classical methods to compare oxidative stress levels and parameters of vascular function in rat models of hypertension, diabetes and nitrate tolerance

Suppression of the JNK Pathway by Induction of a Metabolic Stress Response Prevents Vascular Injury and Dysfunction

Background— Oxidative injury and dysfunction of the vascular endothelium are early and causal features of many vascular diseases. Single antioxidant strategies to prevent vascular injury have met with mixed results. Methods and Results— Here, we report that induction of a metabolic stress response with adenosine monophosphate kinase (AMPK) prevents oxidative endothelial cell injury. This response is characterized by stabilization of the mitochondrion and increased mitochondrial biogenesis, resulting in attenuation of oxidative c-Jun N-terminal kinase (JNK) activation. We report that peroxisome proliferator coactivator 1α is a key downstream target of AMPK that is both necessary and suffici…

European contribution to the study of ROS : A summary of the findings and prospects for the future from the COST action BM1203 (EU-ROS)

WOS: 000410470000009