0000000000004671
AUTHOR
Michael Buerke
PHOSPHODIESTERASE INHIBITORS PIROXIMONE AND ENOXIMONE INHIBIT PLATELET AGGREGATION IN VIVO AND IN VITRO
The phosphodiesterase type III inhibitors piroximone (PIR) and enoximone (ENO) exert positive inotropic and vasodilating effects in patients with severe heart failure. PIR and ENO raise cyclic AMP levels in cardiac and vascular smooth muscle cells. Platelet activity is also regulated by intracellular levels of cyclic AMP. In this study we have investigated the effects of PIR and ENO on platelet activity in vivo and in vitro. PIR and ENO inhibited ADP induced platelet aggregation in a time- and concentration-dependent manner with IC50-values of 67 +/- 14 mumol/l and 129 +/- 6 mumol/l, respectively. Coincubation of PIR with the adenylate cyclase activator iloprost resulted in a synergistic po…
Synergistic Platelet Inhibitory Effect of the Phosphodiesterase Inhibitor Piroximone and Iloprost
Platelet activity is regulated through synthesis and degradation of the intracellular second messengers cAMP or cGMP. The antiplatelet effect of the phosphodiesterase (PDE) III inhibitor Piroximone (PIR) was studied in vitro in platelet rich plasma. ADP induced aggregation was inhibited by PIR with an IC50 of 67 +/- 43 microM. The inhibitory effect was time and dose dependent. The antiaggregatory effects in vivo were studied in anaesthetised rats. Reduction of platelet count following injection of 100 micrograms/kg bw collagen was measured after bolus injection of PIR and vehicle. Piroximone bolus 2 mg/kg bw resulted in a 50% inhibition of platelet aggregation in rats. Cyclic AMP levels in …
Argatroban for elective percutaneous coronary intervention: The ARG-E04 multi-center study
The synthetic arginine-derived direct thrombin inhibitor argatroban is an attractive anticoagulant for percutaneous coronary intervention (PCI), because of its rapid onset and offset, and its hepatic elimination. Argatroban was approved for PCI in patients with heparin-induced thrombocytopenia (HIT). However, there are limited data about argatroban in non-HIT patients. The objective of this open-label, multiple-dose, controlled study was to examine the safety and efficacy of argatroban in patients undergoing elective PCI.Of 140 patients randomized to three argatroban dose groups (ARG250, ARG300, and ARG350 with 250, 300, or 350 μg/kg bolus, followed by 15, 20, or 25 μg/kg/min infusion) and …
Elevated monocyte chemoattractant protein-1 serum levels in patients at risk for coronary artery disease.
Background Monocyte chemoattractant protein-1 (MCP-1) is involved in the recruitment of monocytes into the arterial vessel wall as one of the major events leading to atherosclerotic vascular diseases, such as coronary artery disease (CAD). Methods and Results The study group comprised 263 volunteers aged between 18 and 85 years who were admitted to hospital or clinic for scheduled invasive and non-invasive diagnostic procedures. MCP-1 serum levels were determined using a sandwich-enzyme-linked immunosorbent assay. In each patient, the coronary risk factors (CRF), such as hypertension, high cholesterol, diabetes mellitus, obesity, positive family history, and smoking were evaluated. Low-dens…
Pulmonale Hypertonie bei Linksherzerkrankungen
The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension have been adopted for Germany. While the guidelines contain detailed recommendations regarding pulmonary arterial hypertension (PAH), they contain only a relatively short paragraph on other, much more frequent forms of PH such as PH due to left heart disease. Despite the lack of data, targeted PAH treatments are increasingly being used for PH associated with left heart disease. This development is of concern. On the other hand, PH is a frequent problem that is highly relevant for morbidity and mortality in patients with left heart disease, so that it may be speculated whether selected patients may benefit from…
Anti-inflammatory actions of aprotinin provide dose-dependent cardioprotection from reperfusion injury
Background and purpose: Myocardial injury following ischaemia and reperfusion has been attributed to activation and transmigration of polymorphonuclear leukocytes (PMNs) with release of mediators including oxygen-derived radicals and proteases causing damage. Experimental approach: We studied the serine protease inhibitor aprotinin in an in vivo rabbit model of 1 h of myocardial ischaemia followed by 3 h of reperfusion (MI+R). Aprotinin (10 000 Ukg−1) or its vehicle were injected 5 min prior to the start of reperfusion. Key results: Myocardial injury was significantly reduced with aprotinin treatment as indicated by a reduced necrotic area (11±2.7% necrosis as percentage of area at risk aft…
Intramural delivery of Sirolimus prevents vascular remodeling following balloon injury
Abstract Objective. Several studies have demonstrated that Sirolimus-eluting stents reduce restenosis in patients with coronary artery disease. Here, we tested whether direct delivery of Sirolimus into the vessel wall during balloon angioplasty can modify vascular remodeling over several weeks. Methods and Results. During angioplasty of the rabbit iliac artery we administered an intramural infusion of Sirolimus or its vehicle directly through a balloon catheter into the vessel wall. After 3 weeks neointimal formation was decreased (0.71 ± 0.1 vs. 1.4 ± 0.12 intima/media ratio), and this process was attributed to the inhibitory properties of Sirolimus on ECM deposition and smooth muscle cell…
Two‐dimensional analysis of myocardial protein expression following myocardial ischemia and reperfusion in rabbits
Myocardial ischemia and reperfusion injury (MI/R) can be related to leukocyte activation with subsequent release of cytokines and oxygen derived free radicals. Activation of the complement system has been implicated in the pathogenesis of myocardial ischemia and reperfusion injury. Inflammatory injury will subsequently result in cellular activation and protein synthesis. In the present study we analyzed the myocardial protein expression and its pattern following myocardial ischemia and reperfusion, with and without complement inhibition with the synthetic serine protease inhibitor Futhan/nafamstat mesilate (FUT-175) known to inhibit classical and alternative complement pathway in a rabbit m…
Highly efficient liposome-mediated gene transfer of inducible nitric oxide synthase in vivo and in vitro in vascular smooth muscle cells.
Objective: The efficient introduction of regulatory genes into vascular smooth muscle cells (SMCs) is one of the most promising options for gene therapy of cardiovascular diseases. Cationic liposome-mediated gene transfer may become a favorable transfection technique with regard to patient’s safety for in vivo administration. However, this method until now has its limitation in a low transfection efficiency. Therefore, the present study was designed to improve cationic liposome-mediated transfection of rabbit vascular SMCs in vitro and in vivo, in order to enhance transfection efficiency and present an optimized system which may offer a potential therapeutic benefit for in vivo application.…
Proteome analysis of myocardial tissue following ischemia and reperfusion--effects of complement inhibition.
Myocardial ischemia-reperfusion injury can be related to complement activation with generation of chemotactic mediators, release of cytokines, leukocyte accumulation, and subsequent severe tissue injury. In this regard, activation of transcription factors (i.e., NFkappaB) and de novo protein synthesis or inflammatory protein degradation seems to play an important role. In the present study, we analyzed the cardiac protein expression following myocardial ischemia (60 min) and reperfusion (180 min) in a rabbit model utilizing two-dimensional electrophoresis and nanoHPLC/ESI-MS/MS for biochemical protein identification. To achieve cardioprotective effects, we used a novel highly selective smal…
Fondaparinux and enoxaparin in comparison to unfractionated heparin in preventing thrombus formation on mechanical heart valves in an ex vivo rabbit model
SummaryThe aim of the present study was to investigate the efficacy of three different parenterally administered anticoagulants for the prevention of thrombus formation on artificial heart valves in an experimental rabbit model.Unfractionated heparin was administered intravenously in group I (n = 10), Enoxaparin subcutaneously in group II (n = 10), fondaparinux intravenously in group III (n = 10), and no medication was administered to group IV (n = 9). Leaflets from Sulzer Carbomedics bileaflet mechanical heart valves were placed in a flow chamber. The flow chamber was filled with blood in a continuous circulation between the carotid artery and the jugular vein.In group IV the flow chamber …
Staphylococcus aureus alpha toxin mediates polymorphonuclear leukocyte-induced vasocontraction and endothelial dysfunction.
The effect of Staphylococcus aureus alpha toxin (alpha-toxin) on selectin-mediated neutrophil adhesion was investigated in polymorphonuclear leukocyte- (PMN) induced vasocontraction and endothelial dysfunction. Adherence of human PMNs to rat aortic endothelium increased significantly following stimulation of the endothelium with alpha-toxin (0.1, 0.5, and 1 microg/mL). This effect could be significantly attenuated by monoclonal antibodies directed against P-selectin or fucoidin, a carbohydrate known to block selectins. Unstimulated human PMNs (10(6)cells/mL) were added to organ chambers containing rat aortic rings stimulated with alpha-toxin (0.5 microg/mL). PMNs elicited a significant vaso…
Cardiomyocyte apoptosis is related to left ventricular dysfunction and remodelling in dilated cardiomyopathy, but is not affected by growth hormone treatment.
Background and aims Cardiomyocyte apoptosis (CA) is a common feature of end-stage heart failure. We examined whether CA is associated with cardiac dysfunction and remodelling in heart failure due to dilated cardiomyopathy and studied the effect of human growth hormone (hGH) on CA. Methods and results We studied 38 patients, included in a phase III multi-center, randomised, double-blind and placebo-controlled trial of biosynthetic hGH treatment in dilated cardiomyopathy, at baseline and after 14 weeks treatment. Twenty-six patients received hGH and 12 received placebo. CA was quantified in endomyocardial biopsies using the TUNEL assay. CA correlated with left ventricular size (r=0.43, p=0.00…
Proliferative activity in stenotic human aortocoronary bypass grafts
Abstract Background: Aortocoronary bypass graft disease is responsible for long-term failure of autologous vein grafts. The analyses of proliferation and cell type characterisation in human bypass grafts harvested during re-do surgery make it possible to investigate the cellular processes leading to bypass graft failure. Methods: 30 stenotic vein grafts and 25 control veins were explantated during re-do heart surgery procedures. The total area and cell count of the neointima, media and adventitia were calculated computer-assisted. Actively proliferating cells were identified using antibody to Ki-67 and positive cells were determined by double-label immunocytochemistry with SMC α-actin, CD 3…
Aprotinin inhibits leukocyte–endothelial cell interactions after hemorrhage and reperfusion
Background. The serine protease inhibitor aprotinin has been successfully used to reduce blood loss in patients undergoing cardiac operations. We studied aprotinin for its ability to modulate leukocyte– endothelial cell interactions after ischemia and reperfusion. Methods. The effects of aprotinin on leukocyte– endothelial cell interactions were observed by intravital microscopy in the rat mesenteric microcirculation and immunohistochemical analysis. The inflammatory cascade (leukocyte rolling, firm adherence, and transmigration) was studied after thrombin stimulation and after hemorrhage and reperfusion. Results. Intravenous bolus administration of aprotinin treatment (20,000 U/kg) signifi…
Gene expression profiling of human stenotic aorto-coronary bypass grafts by cDNA array analysis
Objective: Aorto-coronary bypass graft disease with its increasing clinical signification represents an unsolved problem in cardiological and heart surgery practice. Late occlusion of autologous saphenous vein grafts is due to medial and neointimal thickening secondary to migration and proliferation of smooth muscle cells (SMCs) and the subsequent formation of atherosclerotic plaques. This study is aimed at identifying differentially expressed genes in human stenotic bypass grafts to detect unknown pathomechanism and to identify novel targets for prophylactic treatment options. Methods: Stenotic saphenous aorto-coronary bypass grafts ðn ¼ 5Þ were retrieved during re-do aortocoronary bypass …
Simvastatin Inhibits Inflammatory Properties ofStaphylococcus aureusα-Toxin
Background—Simvastatin, a 3-hydroxy-methylglutaryl coenzyme A reductase inhibitor, has been shown to lower serum cholesterol levels in clinical use. Moreover, statins exert beneficial effects in vascular diseases by inhibition of leukocyte rolling, adherence, and transmigration. The aim of this study was to determine if pretreatment with simvastatin attenuatesStaphylococcus aureusα-toxin–induced increase in leukocyte-endothelial interactions during exotoxemia.Methods and Results—The effects of simvastatin on leukocyte-endothelial cell interactions were observed by intravital microscopy in the rat mesenteric microcirculation. Simvastatin (50 or 100 μg/kg) was administered 18 hours before the…
Novel Small Molecule Inhibitor of C1s Exerts Cardioprotective Effects in Ischemia-Reperfusion Injury in Rabbits
Abstract Myocardial ischemia-reperfusion injury can be related to complement activation with generation of chemotactic agents, adhesion molecule expression, release of cytokines and oxygen-derived free radicals, and subsequent neutrophil accumulation. In the present study the cardioprotective effects of a novel highly selective small molecule C1s inhibitor (C1s-INH-248, Knoll) were examined in a rabbit model of myocardial ischemia (I) and reperfusion (R; i.e., 60 min I + 180 min R). In in vitro tests (enzyme activity and SRBC lysis) C1s-INH-248 demonstrated profound inhibitory potency. In vivo C1s-INH-248 (1 mg/kg body weight) administered 5 min before reperfusion significantly attenuated m…
Involvement of PKC and NF-κB in Nitric Oxide Induced Apoptosis in Human Coronary Artery Smooth Muscle Cells
Apoptosis of vascular smooth muscle cells is critically involved in progression of atherosclerosis and may prevent intimal hyperplasia in restenosis and vascular remodeling. Nitric oxide (NO) is known to induce apoptosis, but the signaling pathways still remain unclear. We investigated p53 accumulation, protein kinase C (PKC) activation and nuclear transcription factor (NF-kappaB) binding activity as possible signaling mechanisms of NO-induced apoptosis. Apoptosis was induced dose-dependently with the NO-donors sodiumnitroprusside (SNP: 232+/-48%) and SIN-1 (241+/-90% of actinomycin D induced apoptosis; means +/- SEM, *por =0.05 vs. control) in HSMC. Inhibition of PKC significantly attenuat…
Staphylococcal alpha-toxin provokes neutrophil-dependent cardiac dysfunction: role of ICAM-1 and cys-leukotrienes.
The role of polymorphonuclear neutrophils (PMN) in septic myocardial dysfunction is presently unknown. Staphylococcus aureus infections are frequently associated with septic sequelae. Therefore, we perfused isolated rat hearts with low doses of α-toxin, the major staphylococcal exotoxin, followed by application of human PMN, N-formyl-methionyl-leucyl-phenylalanine, and arachidonic acid. In contrast to sham-perfused hearts (no α-toxin), a rise in coronary perfusion pressure (CPP) and a reduction of contractile function were noted, and cardiac expression of intercellular adhesion molecule (ICAM)-1 was detected by immunohistochemical methods and real-time PCR. Histological analysis and myelope…
Cardioprotective Effects of the Na + /H + Exchange Inhibitor Cariporide in Patients With Acute Anterior Myocardial Infarction Undergoing Direct PTCA
Background —Activation of Na + /H + exchange in myocardial ischemia and/or reperfusion leads to calcium overload and myocardial injury. Experimental studies have shown that Na + /H + exchange inhibitors can attenuate Ca 2+ influx into cardiomyocytes. We therefore performed a multicenter, randomized, placebo-controlled clinical trial to test the hypothesis that inhibition of Na + /H + exchange limits infarct size and improves myocardial function in patients with acute anterior myocardial infarction (MI) treated with direct PTCA. Methods and Results —One hundred patients were randomized to receive placebo (n=51) or a 40-mg intravenous bolus of the Na + /H + exchange inhibitor cariporide (HOE…
Cholesteryl ester transfer protein activity and cardiovascular events in patients with chronic kidney disease stage V.
Background Patients with chronic kidney disease (CKD) have an increased risk for cardiovascular events (CVE). Uraemic dyslipidaemia, which is characterized by low HDL-cholesterol (HDL-C) and elevated triglycerides' levels, may contribute to this elevated cardiovascular risk. Cholesteryl ester transfer protein (CETP) lowers HDL-C by transferring cholesterol esters to LDL and VLDL particles. We tested the hypothesis that CETP activity is associated with CVE in patients with CKD stage V. Methods We measured CETP activity and cholesterol levels in 69 haemodialysis patients. CVE and death were prospectively assessed over a follow-up period of 48 months. Results CETP activity was negatively corre…
Effects of combined therapy of clopidogrel and aspirin in preventing thrombus formation on mechanical heart valves in an ex vivo rabbit model.
Abstract Background: The aim of our study was to investigate the efficacy of the combination of clopidogrel and aspirin in the prevention of thrombus formation on artificial heart valves in an experimental rabbit model as compared to anticoagulation with warfarin. Methods: Studies were performed after oral administration of clopidogrel and aspirin in group I (n=9) for 5 days, after 5±2 days treatment with warfarin in group II (n=9) and without medication in group III (n=9). Leaflets from Sulzer Carbomedics bileaflet valves were placed in a flow chamber. The flow chamber was filled with blood in a continuous circulation between the carotid artery and the jugular vein. Results: In group III, …
NO Reduces PMN Adhesion to Human Vascular Endothelial Cells Due to Downregulation of ICAM-1 mRNA and Surface Expression
Reperfusion damage is largely due to the adherence of polymorphonuclear leukocytes to the endothelium initiated by adhesion molecule upregulation. The reduced endothelial nitric oxide release during ischemia may be involved in the upregulation of intercellular adhesion molecule 1. In this study, we tested if nitric oxide donors suppress polymorphonuclear leukocyte adherence to activated endothelial cells by inhibition of the intercellular adhesion molecule 1 surface expression. Confluent human umbilical vein endothelial cells were stimulated with tumor necrosis factor alpha (300 U/mL) after preincubation with increasing concentrations of the nitric oxide donors CAS 1609 (0.005-5 mM/L) and 3…
Sodium-hydrogen exchange inhibition: novel strategy to prevent myocardial injury following ischemia and reperfusion.
Activation of Na+/H+ exchange and subsequent calcium overload in cardiac myocytes appear to play an important role in myocardial tissue injury following ischemia and reperfusion. Results of several in vitro studies in isolated myocytes and heart preparations and in vivo studies in pigs and rats have suggested that inhibition of Na+/H+ exchange is an effective means to prevent lethal reperfusion injury, arrhythmia, and improve myocardial contractile dysfunction. In patients with acute myocardial infarction (MI), any preventive agent is administered immediately before or shortly after reperfusion, rather than before the occurrence of coronary occlusion. The direct interventional approach to t…
Further evaluation of plasma sphingomyelin levels as a risk factor for coronary artery disease
Abstract Background Sphingomyelin (SM) is the major phospholipid in cell membranes and in lipoproteins. In human plasma, SM is mainly found in atherogenic lipoproteins; thus, high levels of SM may promote atherogenesis. Methods We investigated in a median follow up of 6.0 years the association of SM with the incidence of a combined endpoint (myocardial infarction and cardiovascular death) in stable and unstable patients, and its relation to other marker of atherosclerosis in 1,102 patients with angiographically documented CAD and 444 healthy controls. Results and discussion Logistic regression analysis showed that SM categorized by median was associated with an elevated risk for CAD (HR 3.2…
Cardioprotective effects of the serine protease inhibitor aprotinin after regional ischemia and reperfusion on the beating heart.
AbstractObjective: Early coronary reperfusion of the ischemic myocardium is a desired therapeutic goal to preserve myocardium. However, reperfusion itself contributes to an additional myocardial injury (ie, reperfusion injury), which has been attributed to neutrophil infiltration with subsequent release of proteases and oxygen-derived radicals. We studied the effects of the serine protease inhibitor aprotinin (Trasylol) on myocardial ischemia and reperfusion in a rat model. Methods: The effects of aprotinin (5000 and 20,000 U/kg) were examined in vivo in a rat model of regional myocardial ischemia (20 minutes) and long-term reperfusion (24 hours). Cardioprotecive effects were determined by …
Sodium/hydrogen exchange inhibition with cariporide reduces leukocyte adhesion via P-selectin suppression during inflammation
Background and purpose: The Na+/H+ exchange (NHE) inhibitor cariporide is known to ameliorate ischaemia/reperfusion (I/R) injury by reduction of cytosolic Ca2+ overload. Leukocyte activation and infiltration also mediates I/R injury but whether cariporide reduces I/R injury by affecting leukocyte activation is unknown. We studied the effect of cariporide on thrombin and I/R induced leukocyte activation and infiltration models and examined P-selectin expression as a potential mechanism for any identified effects. Experimental approach: An in vivo rat mesenteric microcirculation microscopy model was used with stimulation by thrombin (0.5 μ ml−1) superfusion or ischaemia (by haemorrhagic shock…
Local administration of antisense phosphorothioate oligonucleotides to the c-kit ligand, stem cell factor, suppresses airway inflammation and IL-4 production in a murine model of asthma.
Abstract Background: The c-kit ligand, stem cell factor (SCF), is an important activating and chemotactic factor for both mast cells and eosinophils. These cells are known to play a fundamental role in the pathogenesis of asthma. Objective: Our goal was to analyze the functional role of SCF in the pathogenesis of asthma. Methods: The expression of SCF was targeted in fibroblasts, epithelial cells, and locally in a murine model of asthma in mice induced by ovalbumin sensitization with an antisense DNA strategy. Results: We could suppress SCF expression in NIH 3T3 fibroblasts and SP1 epithelial cells by a specific antisense phosphorothioate oligonucleotide overlapping the translation start si…
Staphylococcal α-toxin provokes coronary vasoconstriction and loss in myocardial contractility in perfused rat hearts: Role of thromboxane generation
Background —Cardiac performance is severely depressed in septic shock. Endotoxin has been implicated as the causative agent in Gram-negative sepsis, but similar abnormalities are encountered in Gram-positive sepsis. We investigated the influence of the major exotoxin of Staphylococcus aureus, staphylococcal α-toxin, in isolated perfused rat hearts. Methods and Results —α-Toxin 0.25 to 1 μg/mL caused a dose-dependent increase in coronary perfusion pressure that more than doubled. In parallel, we noted a decrease in left ventricular developed pressure and the maximum rate of left ventricular pressure rise (dP/dt max ), dropping to a minimum of <60% of control. These changes were accompani…
Expression of the proto-oncogene c-myc in human stenotic aortocoronary bypass grafts.
Summary Proliferation and differentiation of vascular smooth muscle cells (VSMC) are central events in vascular pathobiology and play a major role in the development of stenotic and restenotic lesions [ 15, 27 ] . The proto-oncogene c-myc and other early cell cycle-regulating genes have been implicated in the induction of cell proliferation and differentiation under diverse pathophysiological conditions [ 11, 13 ] . In the present study we analyzed c-myc mRNAexpression by indirect nonradioactive in situ hybridization technique (NISH) in human stenotic venous bypass grafts (n = 32) retrieved during re-do operations of coronary artery disease and compared the results with 28 native veins (ven…
Neutrophil Adherence to Activated Saphenous Vein and Mammary Endothelium After Graft Preparation
Interaction of circulating leukocytes and vascular endothelium plays an important role in vasoconstriction, endothelial dysfunction, and vascular injury. Dilation procedures of grafts before coronary artery bypass graft surgery might lead to vascular injury and subsequent bypass graft disease.We analyzed in vitro the adherence of fluorescence-labeled polymorphonuclear neutrophils (PMNs) to endothelium of human saphenous vein grafts or internal mammary artery grafts after stimulation with thrombin (0.5 to 2 U/mL) or dilating procedures. Furthermore, we investigated endothelial function of prepared grafts.Thrombin stimulation resulted in a dose-dependent increase of PMN adherence to the endot…
Lokale Medikamentengabe und Gentherapie
Eines der wichtigsten Probleme der klinischen Kardiologie, die Entwickung einer Restenose nach koronarer Ballonangioplastie, ist bisher noch nicht befriedigend gelöst. Die pathophysiologischen Erkenntnisse über die Mechanismen der Neointimabildung sind noch unvollständig, und zahlreiche Therapiestudien mit systemisch applizierten Pharmaka mit unterschiedlichem Wirkungsmechanismus sind fehlgeschlagen. Mögliche innovative Therapieansätze betreffen die hochdosierte lokale Substanzapplikation an der Dilatationsstelle und lokale gentherapeutische Eingriffe zur Verhinderung der Neointimabildung durch Proliferationshemmung der glatten Gefäßmuskelzellen. Zahlreiche Kathetermodelle sind entwickelt w…
Mechanism of reperfusion damage after thrombolysis and ‘direct PTCA’
Summary There is general agreement between cardiologists, that reperfusion of the infarct related coronary artery (PTCA) is the method of choice for the treatment of an acute myocardial infarction. However, the method utilized for inducing a rapid and complete reperfusion is still discussed. Even if thrombolysis will remain the method of choice for the major part of the population, part of the patient cohort with acute infarction will be treated by direct PTCA. Rapid reperfusion of ischemic myocardium reduces infarct size by limiting infarct extension into the entire area at risk, although a reperfusion damage is induced in the core ischemic area. This reperfusion damage has been convincing…
Anti-inflammatory properties of simvastatin on leukocyte-endothelial cell interactions following hemorrhagic shock
Background Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to lower serum cholesterol levels. Recent studies reported that statins have vasculoprotective effects independent of their cholesterol-lowering properties. We studied simvastatin for its ability to modulate leukocyte-endothelial cell interactions under acute inflammation following hemorrhage and reperfusion. Methods The effects of simvastatin on leukocyte-endothelial cell interactions were observed by intravital microscopy in the rat mesenteric microcirculation and by immunohistochemical analyzes. Simvastatin (50 μg/kg or 100 μg/kg) was administrated intraperitoneally 18 h before study. Inf…
Treatment of allergic airway inflammation and hyperresponsiveness by antisense-induced local blockade of GATA-3 expression.
Recent studies in transgenic mice have revealed that expression of a dominant negative form of the transcription factor GATA-3 in T cells can prevent T helper cell type 2 (Th2)-mediated allergic airway inflammation in mice. However, it remains unclear whether GATA-3 plays a role in the effector phase of allergic airway inflammation and whether antagonizing the expression and/or function of GATA-3 can be used for the therapy of allergic airway inflammation and hyperresponsiveness. Here, we analyzed the effects of locally antagonizing GATA-3 function in a murine model of asthma. We could suppress GATA-3 expression in interleukin (IL)-4–producing T cells in vitro and in vivo by an antisense ph…
PLTP activity is a risk factor for subsequent cardiovascular events in CAD patients under statin therapy: the AtheroGene study.
Phospholipid transferprotein (PLTP) mediates both net transfer and exchange of phospholipids between different lipoproteins. Although many studies have investigated the role of PLTP in atherogenesis, the role of PLTP in atherosclerotic diseases is unclear. We investigated the association of serum PLTP activity with the incidence of a combined endpoint (myocardial infarction and cardiovascular death) and its relation to other markers of atherosclerosis in 1,085 patients with angiographically documented coronary artery disease (CAD). In the median follow-up of 5.1 years, 156 patients had suffered from the combined endpoint of myocardial infarction or cardiovascular death including 47 of 395 p…