The Role of Mitochondrial Protein Acetylation in Left Ventricular Function

线粒体蛋白乙酰化在左心室功能中的作用

• 批准号: 9131532
• 负责人: Amanda Stram
• 金额: $ 2.76万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-04 至 2017-08-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9131532
• 关键词: Acetylation; Acyl Coenzyme A; Address; Adult; Biochemical; Biochemistry; Cardiac; Cardiomyopathies; Cardiovascular Diseases; Cause of Death; Cell physiology; Child; Childhood; Data; Deacetylase; Defect; Development; Diabetes Mellitus; Diagnosis; Disease; Disease Progression; Echocardiography; Enzymes; Excision; Familial Hypertrophic Cardiomyopathy; Friedreich Ataxia; Functional disorder; Genetic; Goals; Hand; Health; Heart; Heart Diseases; Heart failure; Histology; Homeostasis; Hypertrophic Cardiomyopathy; Inherited; Investigation; Iron-Binding Proteins; Knockout Mice; Left Ventricular Dysfunction; Left Ventricular Function; Long-Chain-Acyl-CoA Dehydrogenase; Measures; Mechanics; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Mitochondria; Mitochondrial Matrix; Mitochondrial Proteins; Modeling; Molecular; Mus; Myocardial Ischemia; NADH; Obesity; Oxidants; Oxidative Phosphorylation; Pathogenesis; Patients; Physiological; Play; Post-Translational Protein Processing; Prevention strategy; Protein Acetylation; Proteins; Publishing; Reagent; Risk Factors; Role; Signal Transduction; Systemic disease; Testing; Translating; United States; burden of illness; congenital heart disorder; diabetic cardiomyopathy; fatty acid metabolism; frataxin; glucose metabolism; heart function; heart metabolism; hemodynamics; hypertensive heart disease; improved; in vivo; ischemic cardiomyopathy; mouse model; nicotinamide-beta-riboside; overexpression; pyruvate dehydrogenase; therapeutic target; treatment strategy

 DESCRIPTION (provided by applicant): I want to understand the role that mitochondrial protein acetylation plays in the mechanism of heart failure. Heart failure carries a significant disease burden in the United States, with more than half of those with heart failure dying within 5 years of diagnosis. Many prevalent cardiovascular diseases, such as ischemic, hypertensive and diabetic cardiomyopathy, progress relentlessly to heart failure. The mechanisms underlying heart failure are not well understood and require further investigation. Mitochondrial protein acetylation is emerging as an important post-translational modification in cardiovascular diseases, such as that of diabetic and ischemic cardiomyopathy. Sirtuin 3 (SIRT3) is the sirtuin primarily responsible for regulating the acetylation state of proteins in the mitochondria. SIRT3 i a highly conserved NAD+ dependent mitochondrial deacetylase. Its targets include key metabolic enzymes, such as those involved in fatty acid metabolism (long chain acyl CoA dehydrogenase, or LCAD), oxidative phosphorylation (ATP synthase), and glucose metabolism (pyruvate dehydrogenase, or PDH), among others. We have recently shown that SIRT3 is inactivated in a model of congenital hypertrophic cardiomyopathy and heart failure, Friedreich's Ataxia (FRDA) cardiomyopathy. The result is marked hyperacetylation of mitochondrial proteins. We have new evidence that hyperacetylation in these hearts progresses concurrently with worsening heart function. FRDA is an autosomal recessive disease of childhood onset that results in relentlessly progressive neurogenic and cardiogenic dysfunction. Heart failure is the most common cause of death in FRDA. I believe that mitochondrial protein hyperacetylation damages cardiac energy homeostasis by inhibiting activity of key enzymes involved in heart metabolism, and that dysregulated mitochondrial protein acetylation contributes to this heart failure. My project proposes to test this hypothesis by manipulating mitochondrial protein acetylation and measuring cardiac cellular and physiologic function in a mouse model of FRDA, which serves as a model of hypertrophic cardiomyopathy and heart failure. I will manipulate acetylation by increasing SIRT3 activity in FXN-ablated hearts by two mechanisms: Aim I will test the hypothesis that increasing SIRT3 expression will improve heart function in the FRDA model of hypertrophic cardiomyopathy and heart failure. I will use genetic overexpression of SIRT3 in mouse models of FRDA. Aim II will test the hypothesis that increasing NAD+ levels in mitochondria will stimulate SIRT3 activity and improve heart function in the FRDA model of hypertrophic cardiomyopathy and heart failure. I will increase the level of NAD+ in these FRDA mice using a NAD+ precursor. All mice and reagents are in hand. At the end of my two-year proposal, I hope to understand the relationship between protein acetylation and the heart disease of FRDA, and possibly identify SIRT3 as a therapeutic target. My findings in the long term may further our understanding of heart failure and acetylation in other metabolic cardiovascular disease, such as diabetes, metabolic syndrome, and ischemic cardiomyopathy.

 描述（由适用提供）：我想了解线粒体蛋白乙酰化在心力衰竭机理中起着作用。心力衰竭在美国带来了严重的疾病燃烧，其中一半以上患有心力衰竭的人在诊断后的5年内死亡。许多流行的心血管疾病，例如缺血性，高血压和糖尿病性心肌病，无情地发展为心力衰竭。心力衰竭的基础机制尚不清楚，需要进一步研究。线粒体蛋白乙酰化正在成为心血管疾病（例如糖尿病和缺血性心肌病）中重要的翻译后修饰。 Sirtuin 3（Sirt3）是负责控制线粒体中蛋白质的乙酰化状态的Sirtuin原发性。 SIRT3 I高度组成的NAD+依赖性线粒体脱乙酰基酶。它的靶标包括关键的代谢酶，例如参与脂肪酸代谢的酶（长链酰基COA脱氢酶或LCAD），氧化磷酸化（ATP合酶）和葡萄糖代谢（丙酮酸脱氢酶，或PDH）等。我们最近表明，SIRT3在先天性肥厚性心肌病和心力衰竭的模型中被灭活，Friedreich的共济失调（FRDA）心肌病。结果是线粒体蛋白的高乙酰化。我们有新的证据表明，这些心脏中的高乙酰化与后悔的心脏功能同时发展。 FRDA是一种儿童期常染色体隐性疾病，导致无情进行性神经源性和心源性功能障碍。心力衰竭是FRDA中最常见的死亡原因。我认为线粒体蛋白高乙酰化通过抑制与心脏代谢有关的关键酶的活性损害心脏稳态，并且线粒体蛋白乙酰化失调会导致心力衰竭。我的项目建议通过操纵线粒体蛋白乙酰化来检验这一假设，并在FRDA小鼠模型中测量心脏细胞和生理功能，该模型是肥大性心肌病和心脏衰竭的模型。我将通过通过两种机制在FXN启动心脏中增加SIRT3活性来操纵乙酰化：目标我将测试以下假设：在肥厚性心肌病和心脏衰竭的FRDA模型中，SIRT3表达增加将改善心脏功能。我将在FRDA的小鼠模型中使用SIRT3的遗传过表达。 AIM II将检验以下假设：线粒体中的NAD+水平升高将刺激SIRT3活性并改善肥厚性心肌病和心力衰竭的FRDA模型中的心脏功能。我将使用NAD+前体提高这些FRDA小鼠的NAD+水平。所有小鼠和试剂都在手里。在我为期两年的提议结束时，我希望了解蛋白质乙酰化与FRDA的心脏病之间的关系，并可能将SIRT3识别为治疗靶点。从长远来看，我的发现可能会进一步了解其他代谢心血管疾病（例如糖尿病，代谢综合征和缺血性心肌病）的心力衰竭和乙酰化的理解。