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Biomedical subjects

Joël de Leiris

Publications and source records attributed to Joël de Leiris.

15 recordsLinked to original sources
PubMed2006

Protection of endothelial-derived vasorelaxation with cariporide, a sodium-proton exchanger inhibitor, after prolonged hypoxia and hypoxia-reoxygenation: effect of age.

Calcium overload during hypoxia and reoxygenation exerts deleterious effects in endothelial and smooth muscle cells but potential effects of sodium-proton exchanger (NHE) inhibitors have never been investigated in both adult and senescent vessels. Isolated aortic rings from adult and senescent rats were submitted to hypoxia (50 min) or to hypoxia/reoxygenation (20/30 min) without or with cariporide (10(-6) M) and aortic vasoreactivity was recorded. After hypoxia, relaxation to acetylcholine was preserved in adult rings treated with cariporide (-22.3% vs. -9.3% of baseline value in control and treated groups respectively, P<0.05) but not in senescents. Cariporide treatment restored relaxation to acetylcholine after hypoxia-reoxygenation in adult rings (-32.04% vs. -0.03% of baseline value in control and treated groups respectively, P<0.01) and to a lesser extent, in senescent rings (-30.8% vs. -24.4% of baseline value in control and treated groups respectively, P<0.01). These results suggested that hypoxia induced lower acidosis and/or involved other mechanisms of proton extrusion than NHE in senescent aorta. Improvement of endothelial function with cariporide after reoxygenation in senescent aorta, but in a lesser extent than in adult aorta, suggests a lower role of NHE in pH regulation and subsequent calcium overload during aging.

Acetylcholine↗
PubMed2006

Severe impairment of ventricular compliance accounts for advanced age-associated hemodynamic dysfunction in rats.

Advanced aging is associated with hemodynamic dysfunction in rats as in humans. The aim of this study was to assess the mechanisms of development of left ventricular (LV) dysfunction in the rat model of aging. In vivo hemodynamics and ex vivo LV papillary muscle mechanics, myofilaments sensitivity to calcium in skinned fibers and pressure/volume curves in isolated perfused hearts were performed in 3, 24 and 28 month old (mo) male Wistar rats. Hemodynamic dysfunction occurs in 28 mo rats and is characterized by both a systolic and diastolic dysfunction and a LV hypertrophy (+34.7% of LV weight). In papillary muscle, normalized active developed force and myofilament sensitivity to calcium were unchanged between 24 and 28 months of age. In contrast, both resting force/total force ratio in papillary muscle and the slope of the pressure/volume curves in isolated heart are increased between 3 and 24 mo but also between 24 and 28 mo, indicating a progression of the impairment of both papillary muscle stiffness and LV compliance in advanced aging. Hemodynamic dysfunction occurring at advanced age, i.e. 28 mo in rats mainly results from impairment of ventricular compliance resulting from fibrosis.

Actin Cytoskeleton↗
PubMed2005

AT1 receptor blockade prevents cardiac dysfunction after myocardial infarction in rats.

Myocardial infarction (MI) can induce severe alterations of contractile function that can, in turn, lead to heart failure. In a previous study, we have demonstrated that TNF-alpha was involved in cardiac contractile dysfunction 7 days after coronary artery ligation in rats. Since Angiotensin II type 1 (AT1) receptor can be involved in TNF-alpha production, we have investigated whether early short-term treatment with irbesartan, an AT1 receptor blocker, is able to limit TNF-alpha production within the heart and to improve cardiac function and geometry following MI in rats. Male Wistar rats were subjected to permanent coronary artery ligation and received either a placebo or irbesartan (50 mg/kg/day) per os daily from day 3 to day 6 after surgery. On day 7, cardiac TNF-alpha was significantly reduced in MI rats receiving irbesartan (p < 0.05). Moreover, irbesartan improved residual LV end-diastolic pressure under both basal conditions and after volume overload (p < 0.01). In addition, a significant leftward shift of the pressure-volume curve in the irbesartan-treated group was found versus placebo. Finally, infarct expansion index was also significantly improved by irbesartan (p < 0.01). In conclusion, early, short-term AT1 receptor blockade limits post-infarct cardiac TNF-alpha production and diminishes myocardial alterations observed 7 days after MI in the rat.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

Early pre-diabetic state alters adaptation of myocardial glucose metabolism during ischemia in rats.

Pre-diabetic subjects with high insulin secretory capacity have double risk of cardiovascular disease compared with subjects who do not develop insulin-resistance. It is well established that the ability of the myocardium to increase its glycolytic ATP production plays a crucial role in determining cell survival under conditions of ischemia. Up to now, whether the pre-diabetic state reduces the tolerance of the heart to ischemia by affecting its ability to increase its energy production through glycolysis remains unknown. The aim of the present study was to assess whether insulin resistance affects the ability of the myocardium to increase glycolysis under ischemic conditions. Male Wistar rats were fed for 8 weeks a fructose-enriched (33%) diet to induce a pre-diabetic state. Hearts were isolated and subjected to ex-vivo low-flow (2%) ischemia for 30 min. The fructose diet increased sarcolemmal GLUT4 localisation in myocardial cells under basal conditions compared with controls. This effect was not accompanied by increased glucose utilisation. Ischemia induced the translocation of GLUT4 to the plasma membrane in controls but did not significantly modify the distribution of these transporters in pre-diabetic hearts. Glycolytic flux under ischemic conditions was significantly lower in fructose-fed rat hearts compared with controls. The reduction of glycolytic flux during ischemia in fructose-fed rat hearts was not due to metabolic inhibition downstream hexokinase II since no cardiac accumulation of glucose-6-phosphate was detected. In conclusion, our results suggest that the pre-diabetic state reduces the tolerance of the myocardium to ischemia by decreasing glycolytic flux adaptation.

Adaptation, Physiological↗
PubMed2005

Selenium status as determinant of connexin-43 dephosphorylation in ex vivo ischemic/reperfused rat myocardium.

Recent studies have demonstrated that electrical uncoupling at gap junctions during ischemia is associated with cardiac Connexin-43 (Cx43) dephosphorylation. Whether oxidative stress is involved in this phenomenon still remains unclear. In the present study, we examined the influence of selenium intake on reperfusion-induced Cx43 dephosphorylation. Male Wistar rats were fed a diet containing either 0.05 mg/kg (Low-Se, n = 13) or 1.5 mg/kg (High-Se, n = 11) selenium for 8 weeks. At the end of this diet, hearts were isolated and subjected to 10 min regional ischemia followed by 10 min reperfusion. The level of dephosphorylated Cx43 was determined in tissue samples from ischemic/reperfused and non-ischemic regions of the hearts. At the end of the experiemental diet, the activity of the antioxidant enzyme glutathione peroxidase (GSH-Px) was increased in high-Se hearts compared with low-Se hearts (+ 13%; p < 0.05). After ischemia/reperfusion, in low-Se hearts, Cx43 dephosphorylation appeared significantly increased in the left ventricle compared to the non-ischemic right ventricle (+ 149%; p < 0.05). The high-Se diet significantly reduced Cx43 dephosphorylation in the left ventricle (p < 0.05 vs. low-Se diet). In conclusion, our results suggest that oxidative stress may be involved in Cx43 dephosphorylation during myocardial ischemia/reperfusion, thereby contributing to arrhythmogenesis.

Animals↗
PubMed2005

Lipid-lowering drugs and essential omega-6 and omega-3 fatty acids in patients with coronary heart disease.

BACKGROUND AND AIM: There are only little data about the effects of lipid-lowering drugs (LLDs) on the metabolism of essential n-6 and n-3 fatty acids in patients with established coronary heart disease (CHD). METHODS AND RESULTS: Male patients with CHD and high cholesterol levels (>6.2 mmol/L) were randomized (double-blind protocol) to receive either simvastatin 20mg (S) or fenofibrate 200mg daily (F) for 3 months. Dietary habits and plasma fatty acids were not different in the two groups at baseline. After treatment, there were significant changes in both the groups for the main n-6 fatty acids, with an increase in arachidonate (from 6.5+/-1.7% of total fatty acids to 7.5+/-2.1, p<0.001 in S and from 6.2+/-1.4 to 6.8+/-1.4, p<0.005 in F) and a decrease in linoleate (from 26.9+/-3.9 to 24.2+/-3.6, p<0.001, and from 27.8+/-3.4 to 26.1+/-4.2, p<0.05, in S and F, respectively). In addition, there was a decrease in two major n-3 fatty acids (alpha-linolenate and docosahexanoate, both p<0.05), but only in F. CONCLUSIONS: For the first time in a double-blind randomized study in CHD patients, we report that LLDs significantly alter the metabolism of essential fatty acids that are critically important for the pathogenesis and prevention of CHD. Further studies are urgently needed to examine the effects of higher dosages of statins (as currently proposed to reduce more cholesterol) on these essential fatty acids in the clinical setting and the crucial questions of whether specific dietary intervention (combining low intake of n-6 fatty acids and high intake of n-3 fatty acids) may improve the effectiveness of these drugs.

Analysis of Variance↗
PubMed2004

Cardioprotection with cariporide, a sodium-proton exchanger inhibitor, after prolonged ischemia and reperfusion in senescent rats.

This study investigated the effects of cariporide, an inhibitor of sodium-proton exchanger (NHE), during myocardial ischemia and reperfusion in senescence. Isolated Langendorff perfused hearts from 4 (adult) and 24 (senescent) month old male Wistar rats were submitted to prolonged low-flow ischemia (LFI) at 15% of initial coronary flow (180 min) or to 45 min of LFI (15% of initial coronary flow) followed by 30 min of reperfusion, without or with cariporide (10(-6)M). In senescent hearts, but not in adults, treatment with cariporide during prolonged LFI attenuated the elevation of coronary resistances (578 +/- 84 vs 1020 +/- 129% of baseline value after 180 min, P < 0.05) and delayed the decrease in active tension (35.6 +/- 5.1 vs 22.2 +/- 3.4% of baseline value after 60 min; P < 0.05). During reperfusion following LFI, the coronary flow impairment was more pronounced in senescents than in adults (48.4 +/- 9.4 and 75.3 +/- 4.9% of baseline value, respectively; P < 0.05) but was fully prevented in senescent hearts by cariporide treatment (95.6 +/- 17.0% of baseline value; P < 0.05 vs untreated group). This beneficial effect of cariporide on coronary tone was associated with an improvement of active and resting tensions and lower LDH release. Such functional protective effects of cariporide suggest an operative NHE during LFI at both coronary and myocardial levels in senescent heart. In addition, cariporide-associated improvement of post-ischemic recovery of coronary and contractile function as well as the limitation of cellular injury suggests a major role of calcium overload via NHE activation during reperfusion of senescent ischemic heart.

Aging↗
PubMed2004

Cardioprotective effect of chronic low dose ethanol drinking: insights into the concept of ethanol preconditioning.

The reason why low-to-moderate alcohol drinking is associated with reduced cardiovascular mortality is not elucidated. While data suggested that ethanol drinking may have a protective effect on global cardiac ischemia, the effect of chronic low dose ethanol drinking (CLEthD) on myocardial infarct size has not been evaluated in a model of regional ischemia. Using an isolated rat heart model to exclude the effect of various in vivo confounders, we have studied the effect of CLEthD on infarct size (IS) and left ventricular function after 30 min of regional ischemia and 120 min of reperfusion. The effect of CLEthD was compared with ischemic preconditioning (IPC) and protein kinase C (PKC) isoforms were analysed in the myocardium before the 30-min ischemia. Ethanol-fed rats received 9% (v/v) ethanol in their drinking water for 7 weeks. Four groups of rats were studied: (1) control, (2) ethanol, (3) control + IPC, (4) ethanol + IPC. Compared with controls (59 +/- 10), IS (as percent of risk zone) was smaller in the ethanol (39 +/- 6) and IPC (31 +/- 8) groups (both p < 0.05). Combination of ethanol and IPC in the same rats further decreased IS (-46% vs. ethanol, p < 0.05). PKC analyses did not show sustained isoform translocation in that model. These data indicate that chronic low dose ethanol drinking actually induces in the rat heart a chronic protective state that is independent from an effect on the traditional (lipid and coagulation) risk factors. Further studies are required to elucidate the mechanisms of that protection.

Alcohol Drinking↗
PubMed2004

Ethanol, wine, and experimental cardioprotection in ischemia/reperfusion: role of the prooxidant/antioxidant balance.

It is now well established that oxidative stress resulting from reactive oxygen species (ROS) that are generated in cardiac myocytes subjected to ischemia/reperfusion plays a causative role in the development of heart failure and may contribute to promote cell death. During the last decade, several groups have reported that, in animal models of myocardial ischemia/reperfusion, certain nutrients, including ethanol and nonethanolic components of wine, may have a specific protective effect on the myocardium, independent of the classical risk factors implicated in vascular atherosclerosis and thrombosis. Mechanisms through which the consumption of alcoholic beverages protects against ischemia-induced cardiac injury are still unknown. One major open question is whether ethanol and nonethanolic components of wine are cardioprotective, at least in part, by interfering with the myocardial prooxidant/antioxidant balance. Important concepts, such as cardiac preconditioning, are now entering the field of nutrition, and recent experimental evidence suggests that ethanol and/or nonethanolic components of wine might exert preconditioning effects in animal models of myocardial ischemia/reperfusion. There is no doubt that such an observation, if confirmed in human subjects, might open new perspectives in the prevention and treatment of ischemic coronary heart disease.

Animals↗
PubMed2003

Ageing exacerbates the cardiotoxicity of hydrogen peroxide through the Fenton reaction in rats.

Reactive oxygen species (ROS) are involved in the post-ischemic reperfusion syndrome of the myocardium. Moreover, ageing is associated with an increased cardiac sensitivity to both ischemia and reperfusion. The aim of the present study was to determine whether the lower tolerance of aged hearts to reperfusion could be due to an increased sensitivity to the ROS that are produced during the early phase of reperfusion. For this purpose isolated perfused hearts from adult (4 months) and aged (24 months) rats were perfused with a buffer containing 150 microM of hydrogen peroxide (H(2)O(2)) in presence or absence of deferoxamine mesylate (150 microM), an iron chelator. H(2)O(2) perfusion was continued until left ventricular developed pressure had decreased up to 20% of its initial value. Ageing led to a significant reduction of the duration of the H(2)O(2) perfusion required for inducing a 80% functional alteration. Although deferoxamine did not affect this parameter in adult rats, it significantly increased the duration of H(2)O(2)-perfusion in senescent hearts (control: 14.0+/-0.9 min vs. deferoxamine: 18.1+/-1.0, P<0.05). Similarly, ageing aggravated cardiac contracture induced by H(2)O(2)-perfusion. Again, deferoxamine, which had no effect on this parameter in young adult hearts, significantly reduced the contracture of senescent rat hearts. To conclude, our data clearly show that ageing is associated with an increased sensitivity of the myocardium to hydrogen peroxide, which is partly reversed by iron chelation. These results suggest that the iron-catalyzed Fenton reaction producing hydroxyl radicals might be greater in hearts from senescent rats than in hearts from young adults.

Aging↗
PubMed2003

Involvement of reactive oxygen species in cardiac preconditioning in rats.

To date, the involvement of reactive oxygen species in ischemic preconditioning in vivo in rats is not clearly demonstrated. The aim of the present study was to determine whether N-(2-mercaptopropionyl)glycine (MPG), a cell-diffusible hydroxyl radical scavenger, and carnosine, a potent singlet oxygen quencher, could block protection afforded by a single cycle of ischemic preconditioning in vivo in the rat. An ESR study was first performed to validate in vitro the specific antioxidant properties of carnosine and MPG. In a second set of experiments, open-chest rats were subjected to 30 min of left coronary occlusion followed by 60 min of reperfusion. Preconditioning was elicited by 5 min of ischemia and 5 min of reperfusion. Neither MPG (1-h infusion, 20 mg/kg) nor carnosine injection (bolus, 25 micro mol/rat) affected infarct size. The infarct size-limiting effect of preconditioning was completely blunted by MPG, whereas carnosine did not alter the cardioprotection. It is concluded that free radicals and especially hydroxyl radicals could be involved in the adaptive mechanisms induced by a single cycle of preconditioning in vivo in rats.

Animals↗
PubMed2002

Wine drinking and risks of cardiovascular complications after recent acute myocardial infarction.

BACKGROUND: Scientific data on the clinical impact of moderate alcohol consumption after a recent acute myocardial infarction (AMI) are limited, and the specific effect of wine ethanol has not been studied. METHODS AND RESULTS: In survivors of a recent AMI, we analyzed the association between ethanol intake and the risk of recurrence. The patients were classified according to the amount of ethanol that they consumed regularly during follow-up. Major prognostic factors, including the severity of the prior AMI and drug treatment, were recorded and included in the analyses. Only patients with at least 2 reliable assessments of drinking (and dietary) habits were included (n=437). The average ethanol intake was 7.6% of the total energy intake, wherein wine ethanol represented 92% of the total. Among these patients, 104 cardiovascular complications occurred during a mean follow-up period of 4 years. In comparison with abstainers, the adjusted risk of complications was reduced by 59% (95% confidence interval: 17 to 80) in patients whose average ethanol intake was 7.7% of the total energy intake (about 2 drinks/day), and by 52% (95% confidence interval: 4 to 76) in those whose average ethanol intake was of 16% of energy (about 4 drinks/day). CONCLUSION: Whereas moderate wine drinking was associated with a significant reduction in the risk of complications in this homogenous population of coronary heart disease patients, further studies are required to confirm the data, define the clinical and biological profile of the patients who would most benefit from wine drinking after recent AMI, and examine whether the relations found are due to ethanol or other wine ingredients.

Cardiovascular Diseases↗
PubMed2002

Aortic vasoreactivity during prolonged hypoxia and hypoxia-reoxygenation in senescent rats.

To determine the effects of prolonged hypoxia and hypoxia-reoxygenation in senescent blood vessels, isolated aortic rings from 4- and 24-month-old (mo) Wistar rats were submitted to prolonged hypoxia (50 min) or hypoxia/reoxygenation (20 min/30 min) and contractile function recorded. Phenylephrine-induced contraction and sodium nitroprusside- and acetylcholine-induced relaxations were measured after hypoxia or after hypoxia/reoxygenation. In 24 mo group, prolonged hypoxia increased (+83%, P<0.01) and prolonged initial hypoxic contraction, while hypoxic relaxation and delayed contraction were unchanged. Relaxation to acetylcholine was more reduced than in 4 mo group while contraction to phenylephrine and relaxation to sodium nitroprusside were similarly impaired. During reoxygenation, contraction was of same amplitude at both ages and the relaxation to acetylcholine was impaired but to a similar extent in both groups. In conclusion, hypoxic stress induces a greater endothelium-injury in senescent aorta, and increased transient hypoxic contraction, without aggravation of late hypoxic contraction. Aging does not exacerbate the impairment of aortic vasoreactivity after hypoxia-reoxygenation, especially endothelium-dependent relaxation, in sharp contrast to prolonged hypoxia. These age-related changes in vascular sensitivity to oxygen deprivation are different from those observed in coronary arteries, indicating that vasoreactivity during such pathological stress strongly depends on the type of vessel, especially during aging.

Acetylcholine↗