Cellular senescence is a state of irreversible growth arrest induced by various stresses such as oncogenic stimuli. 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. Here we show that endothelial p53 activation plays a pathological role in the regulation of endothelial function and glucose metabolism under diabetic conditions. Endothelial expression of p53 was markedly up-regulated in a streptozotocin-induced diabetes model. Endothelial function such as acetylcholine-dependent vasodilatation was markedly impaired in this model. Although hyperglycemia was not altered, impairment of endothelial function was significantly improved in mice with endothelial cell-specific p53 deficiency. In same way, p53 was markedly activated in ischemic vessels, and endothelial p53 deficiency enhanced ischemia-induced angiogenesis. Mechanistically, endothelial p53 up-regulated the expression of PTEN that negatively regulated the Akt-eNOS pathway, and therefore disruption of p53 improved endothelial dysfunction. We also found that endothelial p53 was markedly activated, and the Akt-eNOS pathway was attenuated in a diet-induced obesity model. Disruption of endothelial p53 activation improved dietary inactivation of eNOS that up-regulated the expression of PGC-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. Consequently, mice with endothelial cell-specific p53 deficiency fed a high-calorie diet showed improvement of insulin sensitivity and less fat accumulation compared with control littermates. These results indicate that endothelial p53 negatively regulates endothelium-dependent vasodilatation, ischemia-induced angiogenesis, and mitochondrial biogenesis by inhibiting the Akt-eNOS pathway and suggest that inhibition of endothelial p53 could be a novel therapeutic target in diabetic patients.
Assembly of the sarcoplasmic reticulum. Biosynthesis of the adenosine triphosphatase in rat skeletal muscle cell culture.