Mechanisms of Endothelial Dysfunction Induced by Aging

Abstract

See related article, pages 692–702 Impaired production or biological activity of nitric oxide (NO) released from vascular endothelium is a central mechanism of endothelial dysfunction.1 Large number of published studies demonstrated that endothelial dysfunction is a hallmark of aged endothelium.2 Currently, increased concentration of superoxide anion in vascular wall is considered a major mechanism of endothelial dysfunction caused by aging.3,4,5 Detrimental effect of superoxide anion on aged endothelium is mediated by its chemical reaction with NO leading to inactivation of NO and production of a very potent oxidant, peroxynitrite.5 At the present time, there is no consensus in the literature regarding the exact source(s) of superoxide anion in aged blood vessels. Endothelial enzymes known to be potent generators of superoxide anion include NADP(H) oxidase, xanthine oxidase, cyclooxygenases, uncoupled endothelial nitric oxide synthases, as well as respiratory chain enzymes in mitochondria.1 Besides increase in superoxide anion production, impairment of endothelial nitric oxide synthase (eNOS) enzymatic activity or reduced antioxidant defense capacity of endothelium may also contribute to elevation of superoxide anion concentration and subsequent endothelial dysfunction.4,5 Optimal intracellular level of amino acid L-arginine, a substrate for eNOS, is a critical factor required for normal biosynthesis of NO. Prior studies by Berkowitz and colleagues6 demonstrated that during aging, increased activity of arginase I, (arginase …