P53 acetylation in microvascular rarefaction and heart failure

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Summary: Coronary microvascular dysfunction (CMD) is a hallmark of hypertension and diabetes. Mitochondrial Sirtuin 3 (SIRT3) is strongly associated with human cardiovascular diseases such as hypertension and diabetes as well as the childhood heart disease of Friedreich’s Ataxia (FRDA). We demonstrate that Sirt3 regulates endothelial (EC) metabolic switch between mitochondrial respiration and glycolysis. Knockout of Sirt3 in EC resulted in a significant decrease in glycolysis, whereas exhibited more prominent production of mitochondrial ROS formation. Disrupting EC metabolism may lead to CMD and impair EC/cardiomyocyte communications which promote hypertensive cardiac hypertrophy. Our study also showed that knockout of Sirt3 in EC resulted in a significant increase in p53 acetylation and exacerbation of pressure-overload induced capillary rarefaction and cardiac hypertrophy. Using a novel p53 acetylation-deficient mutant mouse, we will test our new hypothesis that reduction of Sirt3 promotes p53 acetylation, thus leads to abnormal metabolic reprogramming and mitochondrial (Mito)-ferroptosis. These alterations may promote microvascular rarefaction and cardiac dysfunction. Aim 1: To explore the regulatory role of p53 acetylation in EC glycolytic metabolism and ferroptosis. We will test whether: (a) mutation of p53 acetylation improves glycolysis by reducing TIGAR expression; (b) inhibition of p53 acetylation blunts Mito-ferroptosis in Sirt3KO-EC via TIGAR; and (c) inhibition of p53 acetylation prevents EC ferroptosis/senescence and attenuates cardiomyocyte fibrosis. Aim 2: To define the role of p53 acetylation and ferroptosis in heart failure- associated microvascular rarefaction. Using p53 acetylation and endothelial Sirt3ECKO double knockout mice, we will determine whether mutations of p53 acetylation or inhibition of ferroptosis inhibits ferroptosis and mitochondrial ROS formation, attenuates capillary rarefaction, improves coronary flow reserve (CFR), and reduces cardiac hypertrophy in a pressure-overload induced heart failure mouse model. Aim 3: To define the regulatory role of TIGAR in Sirt3KO-induced ferroptosis and CMD. Using endothelial TIGAREC-KO/Sirt3cKO mice, we will first define TIGAR-dependent EC glycolysis on microvascular rarefaction and diastolic dysfunction in Sirt3cKO mice; Using cardiomyocyte TIGAR-cKO/Sirt3cKO mice, we will further examine TIGAR-dependent cardiomyocyte Mito-acetylation, Mito-Fe2+ and ferroptosis on Sirt3cKO-induced HF. The innovation includes that: (1) identification of p53 acetylation as a novel regulator of EC metabolic reprogramming and Mito- ferroptosis in hypertensive microvascular rarefaction; and (2) elucidate of molecular mechanisms of Mito-TIGAR in the regulation of CMD. Our study has basic and clinical translational significance for the understanding of Sirt3 in human mitochondrial disease such as Friedreich’s Ataxia (FRDA).