Diet modulates endogenous thrombin generation, a biological estimate of thrombosis risk, independently of the metabolic status.

OBJECTIVE: High endogenous thrombin potential (ETP) is associated with venous and arterial thrombosis. Better knowledge of environmental influences on ETP may help to prevent thrombosis. METHODS AND RESULTS: Weaning rats exhibited high ETP values that decreased in low-fat diet and remained elevated on high-fat diet. In adult rats, high-fat diet-induced ETP increase was independent of coagulation factors, obesity, and insulin resistance and negatively associated with polyunsaturated fatty acid levels. Switching from high-fat diet to low-fat diet reversed the procoagulant phenotype with a slower kinetic than the normalization of hyperinsulinemia. In humans, ETP was independent of body weight whereas it was negatively associated with nutritional markers such as the percentage of energy provided by proteins, the protein:fat ratio, circulating phenolic compounds, and omega-3 polyunsaturated fatty acid. A recommended 3-month healthy diet with reduced energy density, including lipids, decreased ETP (-21%; P<0.0001). Changes in ETP were not associated with body weight, insulin sensitivity, or coagulation factor variations, but correlated negatively with plasma docosahexaenoic acid, a nutritional status sensitive fatty acid, and compounds reflecting vegetable intake. CONCLUSIONS: Diet plays a pivotal role in regulating ETP, independently of obesity and insulin resistance. Global nutritional recommendations could be useful in primary prevention of venous thrombosis.

Impact of dietary selenium intake on cardiac health: experimental approaches and human studies.

Selenium, a dietary trace mineral, essential for humans and animals, exerts its effects mainly through its incorporation into selenoproteins. Adequate selenium intake is needed to maximize the activity of selenoproteins, among which glutathione peroxidases have been shown to play a major role in cellular defense against oxidative stress initiated by excess reactive oxygen species. In humans, a low selenium status has been linked to increased risk of various diseases, including heart disease. The main objective of this review is to present current knowledge on the role of selenium in cardiac health. Experimental studies have shown that selenium may exert protective effects on cardiac tissue in animal models involving oxidative stress. Because of the narrow safety margin of this mineral, most interventional studies in humans have reported inconsistent findings. Major determinants of selenium status in humans are not well understood and several nondietary factors might be associated with reduced selenium status. In this review, we discuss recent studies regarding the role of selenoproteins in the cardiovascular system, the effect of dietary intake on selenium status, the impact of selenium status on cardiac health, and the cellular mechanisms that can be involved in the physiological and toxic effects of selenium.

Dietary selenium intake influences Cx43 dephosphorylation, TNF-α expression and cardiac remodeling after reperfused infarction.

SCOPE: Post-infarct left ventricular dysfunction and cardiac remodeling are the primary causes of chronic heart failure in industrialized countries. In the present study, we examined the influence of dietary selenium intake on cardiac remodeling after reperfused myocardial infarction and explored one of the possible mechanisms. METHODS AND RESULTS: Rats were fed a diet containing either 0.05 mg/kg (Low-Se, group of rats receiving the low-selenium diet) or 1.50 mg/kg (group of rats receiving the high-selenium diet) selenium. At the end of the 5th week of the diet, rats were subjected to transient (1 h) coronary ligation followed by 8 days of reperfusion. Infarct size and cardiac passive compliance were increased in the Low-Se group compared with group of rats receiving the high-selenium diet. Similarly, indices of cardiac remodeling (thinning index and expansion index) were more altered in Low-Se hearts. These adverse effects of the Low-Se diet on cardiac remodeling were accompanied by an increase in cardiac TNF-α content, a decreased activity of antioxidant seleno-enzymes and an increase in connexin-43 dephosphorylation. CONCLUSION: Dietary selenium intake influences post-infarct cardiac remodeling even when provided within the range of physiological values. Our data suggest that the cardioprotective effect of selenium might be mediated by a reduced oxidative stress, a lower connexin-43 dephosphorylation, and a decreased TNF-α expression.

Acute administration of l-arginine restores nitric oxide-mediated relaxation in isolated pulmonary arteries from pulmonary hypertensive exercise trained rats.

Hypoxia-induced pulmonary hypertension is associated with an impairment of nitric oxide-mediated vasorelaxation in the pulmonary circulation that is not prevented by exercise training. The present study was designed to test the hypothesis that a decrease in l-arginine bioavailability could be involved in this blunted response to exercise training. Male Wistar rats were randomly assigned to 4 groups: normotensive sedentary, normotensive trained, pulmonary hypertensive sedentary, pulmonary hypertensive trained. Pulmonary hypertension was induced by chronic exposure to hypobaric hypoxia (PIO(2) approximately 90 mmHg). Endothelium-dependent vasorelaxation to acetylcholine (10(-8)-10(-4) M) with or without l-arginine (10(-3) M) and/or nitro-l-arginine methyl ester (5.10(-6) M) was assessed on isolated pulmonary arterial rings. Maximal relaxation to acetylcholine was impaired in both pulmonary hypertensive groups. Acute l-arginine supplementation improved acetylcholine-induced vasorelaxation in the pulmonary hypertensive trained rats (P<0.01), to the level obtained in the normotensive sedentary ones, but not in the pulmonary hypertensive sedentary rats. This improvement was abolished when nitro-l-arginine methyl ester was added to the organ bath and was accounted for by an increase in eNOS protein content. These results confirm that the potential beneficial effect of exercise on nitric oxide-mediated pulmonary artery vasorelaxation is partly blunted by deleterious effects of hypoxia on l-arginine bioavailability. Further studies are needed to evaluate the benefit of the combination of exercise training and l-arginine supplementation for the treatment of pulmonary hypertension.

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.

Preischemic selenium status as a major determinant of myocardial infarct size in vivo in rats.

Prospective epidemiological studies have shown that the incidence of numerous cardiovascular pathologies is correlated with body selenium status. However, it remains unclear whether selenium status also influences the outcome of myocardial infarction. The aim of the present study was to test whether dietary selenium intake affects myocardial necrosis induced by transient regional ischemia in vivo in rats. For this purpose, male Wistar rats received either a high-selenium (High-Se: 1.5 mg of Se/kg) or a low-selenium (Low-Se: 0.05 mg of Se/kg) diet for 10 weeks. Animals were subjected to 30 min of myocardial ischemia induced by coronary artery ligation followed by 60 min of reperfusion. Pre- and postischemic blood samples were collected for glutathione (GSH and GSSG) determination and for glutathione peroxidase (GSH-Px) assessment. Our results show that high-selenium intake reduces myocardial infarct size (High-Se: 25.16 +/- 1.19% versus Low-Se: 36.51 +/- 4.14%, p < 0.05), preserves postischemic GSH/GSSG ratio (High-Se: 1.37 +/- 0.37 versus Low-Se: 0.47 +/- 0.10, p < 0.05), increases plasma GSH-Px activity, and improves postischemic mean arterial pressure. In conclusion, preischemic body selenium status is a major determinant of the outcome of myocardial ischemia in vivo in rats probably because it influences the cellular redox status.

Dietary selenium intake affects cardiac susceptibility to ischaemia/reperfusion in male senescent rats.

BACKGROUND: cardiovascular ageing is associated with an increase in cardiac susceptibility to ischaemia and reperfusion. This has been suggested to be partly related to an increased sensitivity of the myocardium to the reactive oxygen species that are produced during post-ischaemic reperfusion. The aim of the present study was therefore to determine whether increasing cardiac glutathione peroxidase activity by a selenium-enriched diet could afford some protection against ischaemia and reperfusion to senescent rat hearts. METHODS: 22 months old male Wistar rats received either a high-selenium (1.5 mg Se/kg diet) or a low-selenium (0.05 mg Se/kg diet) diet for 10 weeks. At the end of the diet, hearts were submitted to ischaemia and reperfusion ex vivo and either fixed for semi-quantitative analysis of ultrastructural damage by electron microscopy or used for glutathione peroxidase activity assessment. RESULTS: high-selenium supply increased cardiac total, mitochondrial and cytosolic glutathione peroxidase activities. Moreover, this diet induced a significant improvement of cardiac post-ischaemic functional recovery. Finally, this preservation of cardiac function was associated with a significant limitation of ultrastructural alterations of sarcomeres and mitochondria. CONCLUSION: our high-selenium diet considerably limits the sensitivity of senescent rat hearts to ischaemia and reperfusion. This finding suggests that peroxides might play a key role in the increase in cardiac sensitivity to ischaemia and reperfusion during ageing. Together with the observation that selenium status decreases with age in humans, our results indicate that reinforcing selenium supply could improve the prognosis of cardiovascular diseases in old patients.