Post-translational modifications of endothelial nitric oxide synthase induced by oxidative stress in vascular diseases

Abstract

Endothelial nitric oxide (NO) plays a critical role in vascular homeostasis. It regulates the vascular tone, maintains the blood flow, exerts a vasorelaxing effect on smooth muscle cells and inhibits their proliferation. In the endothelium, NO is synthesized by the endothelial NO synthase which is activated by dimerization in the presence of l-arginine (as substrate) and several cofactors including the essential cofactor tetrahydrobiopterin. The NO/eNOS pathway is basically vasculoprotective and antiatherogenic but it may become dysfunctional and proatherogenic under conditions that locally increase the production of reactive oxygen species, leading to tetrahydrobiopterin oxidation, eNOS dysfunction and uncoupling. In these conditions, eNO synthase switches from a NO-producing to superoxide anion-producing enzyme, which potentiates oxidative and nitrosative stress via the generation of peroxynitrite. In redox-perturbed conditions, eNOS dysfunction may also result from post-translational modifications deriving from oxidative stress such as S-glutathionylation or resulting either from the formation of adducts on eNOS by lipid-oxidation-derived aldehydes or from hyperglycemia-induced modifications. In this review, we summarize the mechanisms by which these post-translational modifications alter eNOS activity, and their potential implication in the pathophysiology of vascular diseases.