The Role of Osteoprotegerin and Its Ligands in Vascular Function

International audience; The superfamily of tumor necrosis factor (TNF) receptors includes osteoprotegerin (OPG) and its ligands, which are receptor activators of nuclear factor kappa-B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). The OPG/RANKL/RANK system plays an active role in pathological angiogenesis and inflammation as well as cell survival. It has been demonstrated that there is crosstalk between endothelial cells and osteoblasts during osteogenesis, thus establishing a connection between angiogenesis and osteogenesis. This OPG/RANKL/RANK/TRAIL system acts on specific cell surface receptors, which are then able to transmit their signals to other intracellular comp…

P4613Long-term impact of postnatal nutritional programming on cardiac sensitivity to ischemia-reperfusion injury in vivo and on cardio-protective pathways in mice

Abstract Introduction Nutritional disturbances during the postnatal period may be responsible for a predisposition, or “programming”, to increased cardio-metabolic risk and to a progressive alteration of left ventricular contractility in adulthood. This nutritional perinatal programming may also lead to an alteration of cellular pathways involved in cardiac protection, such as the specific RISK and SAFE pathways, highlighted during pre- and post-ischemic conditioning or those of sirtuins (SIRT), histone deacetylases involved in the regulation of essential biological process. Purpose Our aim was to evaluate in mice the impact of postnatal overfeeding (PNOF) on cardiac sensitivity to ischemia…

P1742Experimental ischemic stroke in rats induce myocardial contractile dysfunction in vivo and ex vivo and increase cardiac vulnerability to ischemia-reperfusion injury ex vivo

0110 : Experimental cerebral ischemia in rats increases myocardial vulnerability to ischemia-reperfusion injury ex vivo

For years, the relationship between cardiac and neurological ischemic events has been mainly attributed to overlapping pathophysiological mechanisms and common risk factors. However, acute stroke may induce dramatic alterations of cardiovascular function. The aim of this work was to evaluate how prior cerebrovascular lesions affect myocardial function in vivo and ex vivo , as well as myocardial vulnerability to ischemic injury. Cerebral embolization was performed in adult Wistar male rats by the injection of microspheres into the left internal carotid artery. Left ventricular function, investigated in vivo using echocardiography (1 hour, 24 hours and 7 days after the embolization), was not …

1203Post-ischemic stroke-induced myocardial dysfunction is associated with nitro-oxidative stress and sympathetic overactivity

0132 : Oxidative stress and cardio-metabolic alterations induced by postnatal programming can be reversed in adulthood by a short-term moderate caloric restriction

Postnatal overfeeding (PNOF) in rodents induces early programming of cardio-metabolic risk. Our aim was to determine if a moderate diet restriction could restore cardio-metabolic alterations induced by PNOF. Immediately after birth, litters of C57BL/6 mice were either maintained at 9 (normal litter, NL), or reduced to 3 (small litter, SL) to induce PNOF. At weaning, all mice received a standard diet ad libitum (AL). At 6 month of age, half of the NL and SL mice were assigned to a moderate 20% calorie restriction (CR: NLCR, SLCR) for one month, while the other mice continued to eat AL (AL: NLAL, SLAL). Glucose and insulin tolerance tests, cardiac function (echocardiography), body composition…

Ischemic stroke increases heart vulnerability to ischemia-reperfusion and alters myocardial cardioprotective pathways

Background and Purpose— For years, the relationship between cardiac and neurological ischemic events has been limited to overlapping pathophysiological mechanisms and common risk factors. However, acute stroke may induce dramatic changes in cardiovascular function. The aim of this study was to evaluate how prior cerebrovascular lesions affect myocardial function and signaling in vivo and ex vivo and how they influence cardiac vulnerability to ischemia-reperfusion injury. Methods— Cerebral embolization was performed in adult Wistar male rats through the injection of microspheres into the left or right internal carotid artery. Stroke lesions were evaluated by microsphere counting, tissue sta…

Postnatal Overfeeding Causes Early Shifts in Gene Expression in the Heart and Long-Term Alterations in Cardiometabolic and Oxidative Parameters

International audience; Background: Postnatal overfeeding (OF) in rodents induces a permanent moderate increase in body weight in adulthood. However, the repercussions of postnatal OF on cardiac gene expression, cardiac metabolism and nitro-oxidative stress are less well known. Methodology/Principal Findings: Immediately after birth, litters of C57BL/6 mice were either maintained at 10 (normal-fed group, NF), or reduced to 3 in order to induce OF. At weaning, mice of both groups received a standard diet. The cardiac gene expression profile was determined at weaning and cardiac metabolism and oxidative stress were assessed at 7 months. The cardiac expression of several genes, including membe…

0131 : Impact of overweight on anthracycline and trastuzumab-induced cardiotoxicity: experimental study in mice

Trastuzumab (TRZ), a humanized monoclonal antibody against Human Epidermal Growth Factor Receptor 2 (HER2) oncogene, is believed to potentiate doxorubicin (DOX) cardiotoxicity, resulting in left ventricular dysfunction. Few data indicate that overweight could influence DOX-induced cardiotoxicity, and no study has already evaluated the impact of moderate overweight on the cardiotoxic effect of DOX alone or in combination with TRZ. Immediately after birth, litters of C57BL/6 mice were either maintained at 10 (normal litter, NL), or reduced to 3 (small litter, SL) in order to induce programming of ~15% overweight through postnatal overfeeding. At 4 months, in order to evaluate the potentiation…

0053 : Short-term moderate diet restriction in adulthood can reverse alterations of cardiac function induced by postnatal overfeeding in mice

Postnatal overfeeding (OF) in rodents induces early programming of cardio-metabolic risk: permanent moderate increase in body weight, metabolic disorders and progressive alterations of cardiac function in adulthood. Our aim was to determine whether moderate diet restriction, performed at the time where these disorders are acquired, could restore cardiac function and ameliorate post-ischemic recovery.Immediately after birth, litters of C57BL/6 mice were either maintained at 9 (normal-fed group, NF), or reduced to 3 in order to induce OF. At weaning, mice of both groups received a standard diet ad libitum (AL). At 6 months of age, half of the NF mice and OF mice were assigned to a moderate 20…

Iron overload does not potentiate doxorubicin induced cardiotoxicity in vivo in mice and in vitro in cardiomyocytes cell cultures

Background: Doxorubicin (DOX), an anticancer anthracycline, is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relations between iron metabolism and DOX-induced cardiotoxicity remain a matter of controversy. Methods: Firstly, we used an in vivo murine model of iron overloading (IO) where male C57BL/6 mice received during 3 weeks (D0-D20) a daily dextran-iron injection (15 mg/kg/day.) and then (D21) a single dose of 6 mg/kg DOX. We evaluated cardiac function with echocardiography, myocardial gene's expression, nitro-oxidative stress levels and iron status. Secondly, the anti-proliferative activity o…

0126: New regulators of iron metabolism, Hepcidin and Erythroferrone, in acute myocardial infarction.

Background Dysfunctional iron storage and transport are common in patients with chronic heart failure and associated with poor prognosis. Body iron could contribute to the pathogenesis of coronary artery disease (CAD) through its ability to induce oxidative stress. However, studies on the relationship between iron metabolism and CAD have yielded conflicting results. Patients and Methods From the obseRvatoire des Infarctus de Cote d’Or (RICO) survey, 31 consecutive patients admitted in Intensive Care Unit for a first AMI were included. Serum concentrations of iron, transferrin, ferritin, the iron-regulatory hormone hepcidin and erythroferrone (a new hepcidin-regulating hormone), transferrin …

The role of osteoprotegerin in the crosstalk between vessels and bone: Its potential utility as a marker of cardiometabolic diseases

International audience; Among the numerous molecules that are being studied for their potential utility as biomarkers of cardiovascular diseases, much interest has been shown in the superfamily of tumor necrosis factor (TNF) receptors. Members of this family include osteoprotegerin (OPG) and its ligands, which are receptor activators of nuclear factor κB ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). These signals may be expressed and regulated, and their functions could be involved in several physiological and pathological processes. The relationship between bone regulatory proteins and vascular biology has attracted attention, and it has been suggested that OPG may medi…

Paradoxically, iron overload does not potentiate doxorubicin-induced cardiotoxicity in vitro in cardiomyocytes and in vivo in mice

Doxorubicin (DOX) is known to induce serious cardiotoxicity, which is believed to be mediated by oxidative stress and complex interactions with iron. However, the relationship between iron and DOX-induced cardiotoxicity remains controversial and the role of iron chelation therapy to prevent cardiotoxicity is called into question. Firstly, we evaluated in vitro the effects of DOX in combination with dextran-iron on cell viability in cultured H9c2 cardiomyocytes and EMT-6 cancer cells. Secondly, we used an in vivo murine model of iron overloading (IO) in which male C57BL/6 mice received a daily intra-peritoneal injection of dextran-iron (15mg/kg) for 3weeks (D0-D20) and then (D21) a single su…

0135 : New regulators of iron metabolism, hepcidin and erythroferrone, in acute myocardial infarction

Background Dysfunctional iron storage and transport are common in patients with chronic heart failure and associated with poor prognosis. Body iron could contribute to the pathogenesis of coronary artery disease (CAD) through its ability to induce oxidative stress. However, studies on the relationship between iron metabolism and CAD have yielded conflicting results. Patients and methods from the obseRvatoire des Infarctus de Cote d’Or (RICO) survey, 31 consecutive patients admitted in Intensive Care Unit for a first AMI were included. Serum concentrations of iron, transferrin, ferritin, the iron-regulatory hormone hepcidin and erythroferrone (a new hepcidinregulating hormone), transferrin s…

Transient postnatal over nutrition induces long-term alterations in cardiac NLRP3-inflammasome pathway.

International audience; Background and aims: The prevalence of obesity is increasing worldwide at an alarming rate. Altered early nutrition, in particular postnatal overfeeding (PNOF), is a risk factor for impaired cardiac function in adulthood. In the understanding of the initiation or progression of heart diseases, NLRP3 inflammasome and non-coding RNAs have been proposed as key players. In this context, the aim of this study was to decipher the role of NLRP3 inflammasome and its post transcriptional control by micro-RNAs in the regulation of cardiac metabolic function induced by PNOF in mice. Methods and results: Based on a model of mice exposed to PNOF through litter size reduction, we …

Calorie Restriction in Adulthood Reduces Hepatic Disorders Induced by Transient Postnatal Overfeeding in Mice

International audience; Impaired early nutrition influences the risk of developing metabolic disorders in later life. We observed that transient postnatal overfeeding (OF) in mice induces long-term hepatic alterations, characterized by microsteatosis, fibrosis associated with oxidative stress (OS), and stress-induced premature senescence (SIPS). In this study, we investigated whether such changes can be reversed by moderate calorie restriction (CR). C57BL/6 male mice pups were maintained during lactation in litters adjusted to nine pups in the normal feeding (NF) group and three pups in the transient postnatal OF group. At six months of age, adult mice from the NF and OF groups were randoml…

Short-term moderate diet restriction in adulthood can reverse oxidative, cardiovascular and metabolic alterations induced by postnatal overfeeding in mice

AbstractWe aimed to determine whether moderate diet restriction could restore cardiac, oxidative and metabolic alterations induced by postnatal overfeeding (PNOF). Litters of C57BL/6 male mice were either maintained at 9 (normal litter, NL), or reduced to 3 (small litter, SL) in order to induce PNOF. At 6 months, half of the NL and SL mice were subjected to 20% calorie-restriction (CR: NLCR, SLCR) for one month, while the other half continued to eat ad libitum (AL: NLAL, SLAL). Six-month old SL mice presented overweight, fat accumulation, hyperleptinemia, glucose intolerance, insulin resistance, increased cardiac ROS production and decreased left ventricular ejection fraction (LVEF). After …

0229: Alterations of cardiac function induced by postnatal overfeeding can be reversed by moderate diet restriction

Postnatal overfeeding (OF) in rodents induces a permanent moderate increase in body weight, metabolic disorders and progressive alterations of cardiac function. Our aim was to determine whether moderate diet restriction could restore cardiac function in mature overfed mice. Immediately after birth, litters of C57BL/6 mice were either maintained at nine (normal-fed group, NF), or reduced to three in order to induce OF. At weaning, mice of both groups received a standard diet ad libitum (AL). At 6 months of age, half of the OF mice were assigned to a moderate 20% calorie restriction (CR, OF-CR) for one month, while NF and the other half of the OF mice continued to eat ad libitum (NF-AL, OF-AL…