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Although the accelerated atherosclerosis and premature aging of the cardiovascular system in patients with metabolic syndrome have been appreciated, the mechanisms of their development and potential therapeutic interventions remain unresolved. Our previous studies implicated advanced glycosylation end products in development of premature senescence preventable with a peroxynitrite scavenger, ebselen. Therefore, the effect of ebselen on endothelial senescence and vasculopathy in a model of metabolic syndrome--Zucker diabetic rats (ZDF)--was investigated. Ebselen decreased the abundance of 3-nitrotyrosine-modified proteins in ZDF rats. A 6-fold increase in the number of senescent endothelial cells in 22-week-old ZDF was prevented by ebselen. Development of vasculopathy, as collectively judged by the acetylcholine-induced vasorelaxation, NO production, angiogenic competence, and number of circulating microparticles, was almost completely prevented when ebselen was administered from 8 to 22 weeks and partially reversed when the treatment interval was 13 to 22 weeks. In conclusion, premature senescence of endothelial cells is progressively rampant in ZDF rats and is associated with the signs of severe vasculopathy. In addition, prevention of premature senescence of vascular endothelium through controlled decrease in nitrotyrosine formation was chronologically associated with the amelioration of vasculopathy, lending support to the idea of the pathogenetic role of premature senescence of endothelial cells in diabetic macrovasculopathy.

Original publication

DOI

10.1161/01.RES.0000111802.09964.EF

Type

Journal article

Journal

Circ Res

Publication Date

20/02/2004

Volume

94

Pages

377 - 384

Keywords

Acetylcholine, Animals, Antioxidants, Aorta, Thoracic, Azoles, Cell Aging, Cell Cycle Proteins, Diabetes Mellitus, Endothelial Cells, Endothelium, Vascular, In Vitro Techniques, Microcirculation, Muscle, Skeletal, Neovascularization, Physiologic, Nitric Oxide, Obesity, Organoselenium Compounds, Rats, Rats, Zucker, Tyrosine, Vasodilation, Vasodilator Agents