P53 acetylation in microvascular rarefaction and heart failure

P53 乙酰化在微血管稀疏和心力衰竭中的作用

• 批准号: 10705328
• 负责人: Heng Zeng
• 金额: $ 38.75万
• 依托单位: UNIVERSITY OF MISSISSIPPI MED CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10705328
• 关键词: Acetylation; Aging; Apoptosis Regulation Gene; Attenuated; Blood capillaries; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cell Death; Childhood; Clinical; Communication; Coronary; Cytosol; Data; Development; Diabetes Mellitus; Endothelium; Exhibits; Fibrosis; Formulation; Friedreich Ataxia; Functional disorder; Glycolysis; Goals; Heart; Heart Diseases; Heart Hypertrophy; Heart failure; Human; Hypertension; Impairment; Inflammation; Iron; Knock-out; Knockout Mice; Laboratories; Lead; Left Ventricular Hypertrophy; Light; Link; Lysine; Metabolic; Metabolism; Microvascular Dysfunction; Mitochondria; Mitochondrial Diseases; Molecular; Mus; Mutant Strains Mice; Mutation; Myocardial dysfunction; Pathogenesis; Pathology; Pathway interactions; Population; Prevalence; Production; Prognosis; Regulation; Respiration; Role; Severities; Signal Pathway; Sirtuins; TP53 gene; Testing; Time; age related; diabetic; drug discovery; erastin; frataxin; hypertensive; improved; innovation; interest; knock-down; mouse model; new therapeutic target; novel; optimal treatments; pressure; prevent; senescence

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).

摘要：冠状动脉微血管功能障碍(CMD)是高血压和糖尿病的标志。 线粒体Sirtuin 3(SIRT3)与人类心血管疾病密切相关，如 高血压和糖尿病以及儿童时期的弗里德里希共济失调(FRDA)心脏病。我们 证明SIRT3调节线粒体呼吸之间的内皮(EC)代谢切换 和糖酵解。在EC中敲除SIRT3导致糖酵解显著减少，而 表现出更显著的线粒体ROS形成。扰乱EC新陈代谢可能 导致CMD并损害EC/心肌细胞通讯，从而促进高血压心脏 肥大。我们的研究还表明，在EC中敲除SIRT3导致了显著的增加 P53乙酰化与压力超负荷所致毛细血管稀疏和心脏病变的加重 肥大。使用一只新的p53乙酰化缺陷突变小鼠，我们将检验我们的新假设 SIRT3的降低促进了P53的乙酰化，从而导致异常的代谢重编程和 线粒体(Mito)-铁性下垂。这些改变可能促进微血管稀疏和心脏 功能障碍。目的1：探讨P53乙酰化在EC糖酵解代谢中的调节作用。 铁性下垂。我们将测试：(A)P53乙酰化突变是否通过减少 TIGAR的表达；(B)通过TIGAR抑制P53乙酰化钝化Sirt3KO-EC的丝裂原铁下垂； 和(C)抑制P53乙酰化可防止EC铁下垂/衰老，并减弱 心肌细胞纤维化。目的2：明确P53乙酰化和铁性下垂在心力衰竭中的作用。 伴发的微血管疏松。使用P53乙酰化和内皮Sirt3ECKO双链 在基因敲除小鼠中，我们将确定是否突变了P53乙酰化或抑制了铁下垂 抑制铁下垂和线粒体ROS的形成，减轻毛细血管疏松，改善 冠脉血流储备(CFR)和减轻压力超负荷诱导心脏的心肌肥厚 故障小鼠模型。目的3：明确TIGAR在Sirt3KO诱导的铁性下垂中的调节作用。 CMD。使用内皮TIGAREC-KO/Sirt3cKO小鼠，我们将首先定义TIGAR依赖的EC 糖酵解对Sirt3cKO小鼠微血管疏松和舒张期功能障碍的影响 心肌细胞TIGAR-CKO/Sirt3cKO小鼠，我们将进一步检测TIGAR依赖的心肌细胞 Sirt3cKO诱导的HF中铁下垂与Mito-乙酰化、Mito-Fe2+的关系。创新之处包括：(1) P53乙酰化是EC代谢重编程和丝裂原活化的新调节因子 高血压微血管疏松的铁性下垂；以及(2)阐明高血压微血管疏松的分子机制。 MITO-TIGAR在CMD的调控中。我们的研究具有基础和临床的翻译意义 SIRT3在人类线粒体疾病如Friedreich共济失调(FRDA)中的作用