Abstract-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. Key Words: metabolic syndrome Ⅲ macrovasculopathy Ⅲ nitric oxide Ⅲ vasorelaxation Ⅲ peroxynitrite A therosclerosis is responsible for the death of 80% of patients with diabetes, compared with only 30% in the general population of North America. 1 Although the accelerated atherosclerosis and premature aging of the cardiovascular system in patients with diabetes mellitus and metabolic syndrome X have long been appreciated, the mechanisms of their development and potential therapeutic interventions remain not fully understood. Several main concepts attempt to explain the phenomenon of premature aging of the cardiovascular system by ascribing it to the oxidative stress and mitochondrial dysfunction, advanced glycosylation end products (AGE) activating a cognate receptor, RAGE, and activation of protein kinase C-␤. [2][3][4][5] These metabolic abnormalities lead to the increased incidence of apoptosis in endothelial cells, a possible contributor to the accelerated atherosclerosis. 6 And yet a mechanistic view on the progression from oxidative stress to overt vasculopathy is missing. This study seeks to provide experimental evidence in support of an idea that premature endothelial cell senescence may represent a critical intermediate step between oxidative stress and vasculopathy.Our previous studies of endothelial cells subjected to a microenvironment emulating diabetic milieu in that it contains AGE-modified long-lived extracellular matrix protein glycated collagen I (GC) revealed dec...

TNF-alpha levels were significantly higher in the soleus and EDL muscles, but not in the epididymal fat, in the FFRs compared with the control rats. Temocapril and CS-866 lowered systolic blood pressure, improved insulin resistance, and reduced TNF-alpha in both skeletal muscles. There were significant negative correlations between M values and TNF-alpha levels in both soleus and EDL muscles. Also, the soleus muscle strip incubation with 10(-7) mol/l angiotensin II increased TNF-alpha secreted into the incubation medium compared to the incubation without angiotensin II. These results suggest that skeletal muscle TNF-alpha is linked to insulin resistance and hypertension and that angiotensin II may be one of the factors that regulate skeletal muscle TNF-alpha.