Gamma-tocopherol may promote effective no synthase function by protecting tetrahydrobiopterin from peroxynitrite

Oxidation of tetrahydrobiopterin by peroxynitrite in oxidant-stressed endothelium compromises nitric oxide synthase (eNOS) activity while amplifying superoxide production; this mechanism contributes prominently to the endothelial dysfunction that characterizes many common clinical disorders. As a physiological peroxynitrite scavenger, gamma-tocopherol may have the potential to protect tetrahydrobiopterin and thus preserve effective eNOS activity. Indeed, in clinical studies, supplemental gamma-tocopherol has enhanced platelet eNOS activity, and a diet high in gamma-tocopherol-rich walnuts has improved endothelium-dependent vasodilation in hypercholesterolemia. In rodents, gamma-tocopherol is reported to increase arterial expression of eNOS while up-regulating an activating phosphorylation of this enzyme. Although epidemiological efforts to link gamma-tocopherol status with coronary risk have yielded inconsistent findings, this does not rule out the possibility that high intakes of this antioxidant could provide clinical protection. The impact of supplemental gamma-tocopherol on compromised endothelium-dependent vasodilation in various disorders merits examination.