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(申请人提供)：我想了解线粒体蛋白乙酰化在心力衰竭机制中所起的作用。在美国，心力衰竭是一种严重的疾病负担，超过一半的心力衰竭患者在确诊后5年内死亡。许多常见的心血管疾病，如缺血性、高血压和糖尿病心肌病，都会无情地发展为心力衰竭。心力衰竭的机制还不是很清楚，需要进一步的研究。线粒体蛋白乙酰化是心血管疾病中的一种重要的翻译后修饰，如糖尿病和缺血性心肌病。Sirtuin 3(SIRT3)是一种sirtuin，主要负责调节线粒体中蛋白质的乙酰化状态。SIRT3I是一种高度保守的依赖NAD+的线粒体脱乙酰酶。它的目标包括关键的代谢酶，如与脂肪酸代谢有关的酶(长链酰辅酶A脱氢酶，LCAD)、氧化磷酸化(ATP合成酶)和葡萄糖代谢(丙酮酸脱氢酶，PDH)等。我们最近发现SIRT3在先天性肥厚型心肌病和心力衰竭，Friedreich‘s Aaxia(FRDA)型心肌病的模型中是失活的。其结果是线粒体蛋白质的显著超乙酰化。我们有新的证据表明，这些心脏中的过乙酰化与心功能恶化同时进行。FRDA是一种儿童起病的常染色体隐性疾病，导致无情的进行性神经源性和心源性功能障碍。心力衰竭是FRDA最常见的死亡原因。我认为线粒体蛋白超乙酰化通过抑制参与心脏代谢的关键酶的活性来破坏心脏能量平衡，而线粒体蛋白乙酰化失调是导致这种心力衰竭的原因之一。我的项目建议通过操纵线粒体蛋白乙酰化和测量FRDA小鼠模型的心脏细胞和生理功能来验证这一假设，FRDA模型是肥厚性心肌病和心力衰竭的模型。我将通过增加FXN消融心脏中SIRT3的活性来操纵乙酰化，通过两种机制：目的我将在肥厚性心肌病和心力衰竭的FRDA模型中验证增加SIRT3表达将改善心功能的假设。我将在FRDA的小鼠模型中使用SIRT3的基因过表达。目的II将在FRDA肥厚型心肌病心力衰竭模型上验证线粒体NAD+水平升高会刺激SIRT3活性和改善心功能的假说。我将使用NAD+前体提高这些FRDA小鼠的NAD+水平。所有的老鼠和试剂都在掌控之中。在我为期两年的计划结束时，我希望了解蛋白质乙酰化与FRDA心脏病的关系，并可能确定SIRT3作为治疗靶点。从长远来看，我的发现可能会加深我们对其他代谢性心血管疾病，如糖尿病、代谢综合征和缺血性心肌病中心力衰竭和乙酰化的理解。