Scavenging of peroxynitrite-derived radicals by flavonoids may support endothelial NO synthase activity, contributing to the vascular protection associated with high fruit and vegetable intakes

SummaryAmple intakes of fruit and vegetables have been linked epidemiologically with reduced risk for coronary disease, stroke, hypertension, obesity, many types of cancer, chronic pulmonary disease, osteoporosis, and various ocular disorders. The favorable impact of diets rich in fruit and vegetables on coronary risk has been confirmed in meta-analyses, and is thought to be largely attributable to the folk acid and potassium supplied by these foods. Although high intakes of vitamin C appear to confer some cardiovascular protection, the amounts supplied by typical diets may be too low to be of much benefit in this regard. High flavonoid intakes emerge as protective in some epidemiological studies, albeit the dose–response pattern observed is often L-shaped – seemingly more consistent with low intakes being harmful, than with high intakes being protective. Nonetheless, flavonoids have shown anti-atherogenic activity in rodent models, and both clinical and rodent supplementation studies with foods and food extracts rich in flavonoids demonstrate improvements in endothelium-dependent vasodilation traceable to increased endothelial nitric oxide synthesis. However, flavonoids do not appear to increase the expression of endothelial NO synthase, nor do they modify endothelial superoxide production. A likely explanation is that, even in nanomolar concentrations achievable in vivo, flavonoids can act as efficient scavengers of peroxynitrite-derived radicals, thereby protecting the cofactor tetrahydrobiopterin, crucial for NO synthase activity. Studies with cultured endothelial cells should be useful for evaluating this possibility. It would also be appropriate to assess the effects of flavonoids on prostacylin synthetase activity, on endothelial catabolism of asymmetric dimethylarginine, and on signaling mechanisms that activate NO synthase. Since peroxynitrite can induce mutagenic damage to DNA, it is conceivable that scavenging of peroxynitrite-derived radicals contributes to the reduction in mutagenesis associated with high intakes of fruits and vegetables. Carotenoids also have the potential to prevent peroxynitrite-mediated damage, although, as contrasted with flavonoids, there is comparatively little evidence that these compounds are anti-atherogenic or beneficial for endothelial function; a recent meta-analysis of epidemiological studies suggests that high lutein intakes may modestly reduce coronary risk.