Oxidants downstream from superoxide inhibit nitric oxide production by vascular endothelium – a key role for selenium-dependent enzymes in vascular health

Abstract 

Although superoxide can directly quench endothelium-generated nitric oxide (NO), there is considerable evidence that oxidants derived from superoxide – notably peroxides and their further derivatives – can also impair NObioactivity. In part, this reflects inhibition of NO synthase activity, perhaps mediated by the oxidation of labile sulfhydryl groups, as well as the activation of protein kinase C. Selenium deficiency exacerbates these effects, presumably owing to the crucial role of selenium-dependent thioredoxin reductase and glutathione peroxidases in preventing and reversing oxidant damage to proteins. High–normal homocyst(e)ine levels may induce an ‘effective selenium deficiency’' by suppressing glutathione peroxidase transcription in endothelial cells. Considerable epidemiology, primarily of European origin, points to mediocre selenium nutrition as a significant vascular risk factor; the risk associated with elevated plasma homocyst(e)ine levels is now well established. In addition to preventing LDL oxidation, vitamin E can be expected to minimize the contribution of lipid peroxides to endothelial dysfunction. Lipoic acid, which can function in vivo as a versatile antioxidant and sulfhydryl reductant, may have particular value for protecting endothelium from oxidants; its clinical utility in diabetic neuropathy may reflect this benefit. Good selenium status, as well as supra-nutritional intakes of lipoic acid, may down-regulate cytokine-mediated endothelial activation by helping to maintain the proper structure of oxidant-labile proteins – such as tyrosine phosphatases – that modulate this signaling. It can be concluded that a number of supplemental nutrients – including selenium, vitamin E, lipoic acid, and the vitamins that promote catabolism of homocysteine – have the potential to promote vascular health by mitigating the adverse impact of superoxide-derived oxidants on endothelial function

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