Inflammation and endothelial dysfunction with aging

Abstract

Aging is an independent risk factor for cardiovascular disease that is associated with chronic inflammation. The turnover of the endothelial layer is accelerated in aged subjects and endothelial dysfunction is observed after regeneration. Such dysfunction is the first stage of vascular disease. It is characterized by a reduced availability of nitric oxide (NO, an important mediator that inhibits vasomotor tone), thrombosis and vascular inflammation. The reduced availability of NO associated with aging not only results in blunted endothelium-dependent vasodilatations, but also leads to sequential oxidative and pro-inflammatory events that ultimately facilitate the occurrence of atherosclerosis. Increased intracellular oxidative stress is due not only to the augmented expression of oxidant-generating enzymes, such as NADPH oxidase, xanthine oxidase and uncoupled endothelial NO synthase, but also to the down-regulation of endothelial anti-oxidative enzymes, in particular mitochondrial superoxide dismutases. Consequently, the accumulated oxidative stress causes modifications of key proteins (nitrosylation by peroxynitrite), facilitation of the production of endothelium-dependent vasoconstrictor prostanoids and activation of stress-responsive mechanisms (transcription factors in particular nuclear factor kB). These events initiate a proinflammatory response, a key initial event in the genesis of the atherosclerotic plaque.