Role of p53 Acetylation in Mediating Myocardial Angiogenesis and Diabetic Cardiomyopathy

The prevalence of diabetic heart failure (HF) is increasing at an alarming rate, it is therefore urgent to identify potential therapeutic targets. Accumulating evidence demonstrates the important role of acetylation of mitochondrial proteins in HF and diabetes. In this study, we investigated the role of p53 acetylation in diabetic impairment of myocardial angiogenesis and determine whether inhibition of p53 acetylation can improve cardiac function in the setting of diabetes. The acetylation of p53 was significantly increased in hearts of diabetic db/db mice, hyperglycemic STZ mice, and high fat-diet-induced obese mice, which was associated with the reduced level of SIRT3. Knockout of SIRT3 increased p53 acetylation, which in turn led to impairment of angiogenesis and cardiac function in mice. Using cultured cardiomyocytes exposed to high glucose (HG) and diabetic db/db mice, we further explored the roles of p53 acetylation on angiogenic growth factor expression, angiogenesis and cardiac function. We found that exposure of cardiomyocytes to HG resulted in upregulation of p53 acetylation. This was accompanied by a reduction of Sirt3 expression. Transfection with Ad-Sirt3 significantly reduced hyperglycemia-induced p53 acetylation. Overexpression of Sirt3 increased the expression of HIF-1α and Ang-1 and VEGF, together with reduction of oxygen consumption and ROS formation. Hyperglycemia-induced caspase-3 expression and apoptosis was also significantly suppressed by Sirt3. Knockdown of p53 in cardiomyocytes by using siRNA significantly increased the expression of HIF-1α and Ang-1 and VEGF. Treatment with p53 siRNA significantly decreased oxygen consumption. In vivo , Ad-Sirt3 treatment significantly inhibited p53 acetylation in the heart of db/db mice. Ad-Sirt3 treatment upregulated the expression of HIF-1α, Ang-1 and VEGF. Similarly, mutations at acetylation sites K117/161/162 and K98 of p53 (p53 4KR ) upregulated the expression of HIF-1α and increased angiogenesis in mouse heart. Ad-Sirt3 treatment increased angiogenesis, and reduced ROS formation and apoptosis in the diabetic heart. These led to significantly improved cardiac function. Our study suggests that p53 acetylation may be a novel target for diabetic cardiomyopathy.