Abstract 10640: Vascular Senescence Promotes the Development of Insulin Resistance: Role of Endothelial p53 in Glucose Metabolism
Cellular senescence is a state of irreversible cell growth arrest induced by excessive replication or various stresses such as oncogenic stimuli. It is thought to be a defensive mechanism against malignant transformation. This response is controlled by negative regulators of the cell cycle like the p53 tumor suppressor protein. Accumulating evidence has suggested a role of p53 activation in various age-associated conditions including atherosclerosis, heart failure and diabetes. It has also been reported that diabetes promotes vascular senescence and accelerates the development of cardiovascular complications. However, it remains unclear whether the senescence of vascular cells per se contributes to metabolic abnormalities in diabetic patients. Here we identified a crucial role of endothelial p53 activation in the regulation of glucose homeostasis. Endothelial expression of p53 was markedly up-regulated when mice were fed a high-calorie diet. To investigate the role of endothelial p53 in type 2 diabetes, we established the mice with endothelial cell-specific p53 deficiency on a high-calorie diet. Disruption of endothelial p53 activation improved dietary inactivation of endothelial nitric oxide synthase that regulated the expression of peroxisome proliferator-activated receptor-γ coactivator-1α in skeletal muscle, thereby increasing mitochondrial biogenesis and oxygen consumption. Inhibition of endothelial p53 also improved dietary impairment of glucose transport into skeletal muscle by up-regulating endothelial expression of glucose transporter 1. Endothelial p53 deficient mice showed improvement of insulin sensitivity and less fat accumulation compared with control littermates. These results indicate that endothelial p53 regulates glucose metabolism by modulating mitochondrial biogenesis and glucose uptake in skeletal muscle and suggest that inhibition of endothelial p53 could be a novel therapeutic target to block the vicious cycle of cardiovascular and metabolic abnormalities occurring in diabetic patients.
- © 2012 by American Heart Association, Inc.