Abstract 1006: Activation of SIRT1, a Longevity Gene, Prevents the Development of Diabetic Vasculopathy by Inhibiting Endothelial Senescence
Diabetic macroangiopathy is one of the most important complications of diabetes, but the mechanisms underlying the development of diabetic vasculopathy are still largely unknown. Restriction of calorie intake (CR) is known to extend the longevity of organisms ranging from yeast to mice and to prevent age-related conditions. In yeast, CR extends lifespan by increasing the activity of Sir2, an NAD+-dependent deacetylase. SIRT1, a human homolog of Sir2, has been reported to inhibit p53 activity, thereby positively regulating cellular lifespan. We previously showed that treatment with high glucose (HG) induced the senescence of human endothelial cells by decreasing SIRT1 activity. Here we report that SIRT1 activity is critically involved in the pathogenesis of diabetic vasculopathy. As a consequence of treatment with HG, endothelial cells exhibited evidence of vascular dysfunction such as increased expression of pro-inflammatory adhesion molecules. Such impairment was significantly prevented by introduction of SIRT1, suggesting that activation of this molecule might improve vascular dysfunction in diabetic mice. To test this hypothesis, we produced a diabetic mouse model by intraperitoneal injection of streptozotocin and treated the mice with resveratrol, a potent SIRT1 activator. Hyperglycemia promoted in vivo cellular senescence as demonstrated by increased expression of p53 and p21 in the aorta. Consistent with these observations, expression of SIRT1 was markedly decreased, while expression of pro-inflammatory adhesion molecules was induced in the aorta of diabetic mice. Consequently, the number of rolling leukocytes in the arteries was significantly increased compared with non-diabetic mice. Treatment of diabetic mice with resveratrol effectively prevented activation of the p53/p21 signaling pathway by hyperglycemia without a direct effect on plasma glucose levels. Resveratrol treatment markedly decreased arterial expression of pro-inflammatory adhesion molecules and thus ameliorated an increase of leukocyte rolling and adhesion in diabetic mice. These results disclose a novel mechanism of diabetic vascular dysfunction and suggest that SIRT1 is a potential therapeutic target for the treatment of diabetic vasculopathy.