Enhanced Peroxynitrite Formation Is Associated with Vascular Aging

作者：Bernd van der Loo, Ralf Labugger, Jeremy N. Skepper, Markus Michael Bachschmid, Juliane Kilo, Janet M. Powell, Miriam Palacios‐Callender, Jorge D. Erusalimsky, Thomas Quaschning, Tadeusz Maliñski, Daniel Gygi, Volker Ullrich, Thomas Felix Lüscher · 发表于：The Journal of Experimental Medicine · 年份：2000 · DOI：10.1084/jem.192.12.1731 · 被引用次数：675 · 研究领域：Nitric Oxide and Endothelin Effects、Renin-Angiotensin System Studies、Eicosanoids and Hypertension Pharmacology

Vascular aging is mainly characterized by endothelial dysfunction. We found decreased free nitric oxide (NO) levels in aged rat aortas, in conjunction with a sevenfold higher expression and activity of endothelial NO synthase (eNOS). This is shown to be a consequence of age-associated enhanced superoxide (.O(2)(-)) production with concomitant quenching of NO by the formation of peroxynitrite leading to nitrotyrosilation of mitochondrial manganese superoxide dismutase (MnSOD), a molecular footprint of increased peroxynitrite levels, which also increased with age. Thus, vascular aging appears to be initiated by augmented.O(2)(-) release, trapping of vasorelaxant NO, and subsequent peroxynitrite formation, followed by the nitration and inhibition of MnSOD. Increased eNOS expression and activity is a compensatory, but eventually futile, mechanism to counter regulate the loss of NO. The ultrastructural distribution of 3-nitrotyrosyl suggests that mitochondrial dysfunction plays a major role in the vascular aging process.