Role of SIRT3 in alcoholic heart muscle disease

SIRT3 在酒精性心肌病中的作用

基本信息

批准号：
8444091
负责人：
CHARLES H. LANG
金额：
$ 21.99万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444091
关键词：
ATP2A2 Address Adult Agonist Alcohol abuse Alcohol consumption Alcoholic Cardiomyopathy Alcoholism Alcohols Area Biochemical Cardiac Cardiac Myocytes Cardiomyopathies Cessation of life Chronic Clinical Collagen Collection Connective Tissue Coupled Data Deacetylase Defect Deposition Development Diagnosis Diet Dilated Cardiomyopathy Drug abuse Endothelial Cells Etiology Exhibits Extracellular Matrix Fibroblasts Fibronectins Fibrosis Functional disorder Goals Heart Heart Diseases Heart Hypertrophy Heart failure Heavy Drinking Hospitals Human In Vitro Incubated Individual Infusion procedures Knockout Mice Knowledge Literature M-Mode Echocardiography Matrix Metalloproteinases Mediator of activation protein Metabolic Metabolism Modeling Molecular Monitor Morbidity - disease rate Mus Muscle Cells Myocardial Myocardium Myofibroblast Myopathy Myosin Heavy Chains Organ Outcome Outcomes Research Pathogenesis Pathology Patients Physiological Population Production Protein Family Protein Isoforms Proteins Public Health Recovery Research Rodent Rodent Model Role Seminal Sir2-like Deacetylases Sirtuins Smooth Muscle Actin Staining Method Structure Therapeutic Time Wild Type Mouse Work alcohol effect base body system cardiovascular disorder risk cell transformation cell type chronic alcohol ingestion clinically significant design feeding heart function in vivo insight interstitial member mortality novel outcome forecast patient population premature prevent public health relevance response small molecule therapeutic development transdifferentiation

项目摘要

DESCRIPTION (provided by applicant): Alcohol abuse is a major public health problem leading to premature death, impaired hospital recovery, and the dysfunction of multiple organ systems. Alcoholic heart muscle disease (AHMD.) is a hallmark of sustained alcohol abuse and the associated cardiomyopathy is diagnosed in nearly a third of those individuals who chronically abuse alcohol. The mechanisms leading to AHMD are undoubtedly multifactorial, involving both cardiac myocytes and fibroblasts. Whereas the preponderance of research to date on AHMD has involved changes in cardiac muscle per se, over time the accumulation of collagen and extracellular matrix (ECM) in the heart may represent a central mechanism contributing to pathogenesis. As such, elucidation of the cellular and molecular mechanisms regulating cardiac myofibroblast conversion and activation in response to prolonged alcohol intake is of clinical significance. Our long-term goal is to elucidate the etiology and pathogenesi of AHMD.. Our preliminary data indicate that chronic (24 wk) alcohol consumption in mice produces definitive evidence for the transdifferentiation of cardiac fibroblasts to myofibroblasts (myoFBs), a cellular transition associated with increased collagen deposition (e.g., fibrosis) and cardiac contractile dysfunction. Hearts from alcohol-fed mice also show a decrease in sirtuin (SIRT)-3, a protein deacetylase which has emerged as an important member of a protein family regulating cell transformation and metabolism. Finally, we have discovered chronic alcohol consumption increases the ¿- to ¿-myosin heavy chain (MHC) ratio in cardiomyocytes. Therefore, based on these preliminary data and information present in the literature, we hypothesize that AHMD is caused by a decrease in SIRT3. We posit this change subsequently stimulates the transformation of cardiac fibroblasts to myoFBs, thereby enhancing collagen deposition and interstitial fibrosis, which ultimately impairs cardiac function. To address the questions implicit in this hypothesis, the proposed research has the following specific aims: (1) To delineate whether the alcohol-induced decrease in cardiac SIRT3 is causally related to ECM turnover and a mediator of AHMD.; and (2) To determine whether in vivo activation of SIRT3 prevents the development of AHMD.. Our application exploits the availability of a murine model of cardiac-specific SIRT3 over-expression and is supported by exciting preliminary data. Our focus on state-of-the-art in vivo approaches permits us to definitively assign physiological importance to our observations. To maintain the focus of the current application, in vitro studies are not specifically proposed. However, preliminary data are available indicating that alcohol also decreases SIRT3 and increases ECM production in cultured human cardiac fibroblasts, suggesting a direct effect of alcohol on this cell type. The expected research outcomes will contribute fundamental knowledge pertaining to the metabolic effects of SIRT3 and provide seminal mechanistic insights into the clinically significant pathology of AHMD., thereby providing a broad translational basis for our research focus and the potential for therapeutic development.

描述（由适用提供）：酗酒是导致过早死亡，医院恢复受损以及多器官系统功能障碍的主要公共卫生问题。酒精性心肌疾病（AHMD。）是持续酒精滥用的标志，相关的心肌病被诊断出在长期滥用酒精的人中几乎有三分之一。导致AHMD的机制无疑是多因素的，涉及心肌细胞和成纤维细胞。迄今为止，在AHMD上进行的研究涉及心脏肌肉本身的变化，但随着时间的流逝，胶原蛋白和细胞外基质（ECM）在心脏中的积累可能代表了有助于发病机理的核心机制。因此，阐明了响应长时间酒精摄入的细胞和分子机制，用于响应心脏成肌纤维细胞转化和激活是临床意义。我们的长期目标是阐明AHMD的病因学和病原体。我们的初步数据表明，小鼠的慢性（24周）饮酒会产生明确的证据，以证明心脏成纤维细胞对肌纤维细胞（Myofbs）（Myofbs）的转变（一种与collagen collagen deprestion contragen Fibrise（E.G.G.G.G.）相关的细胞过渡。饮酒小鼠的心脏还显示出蛋白脱乙酰基酶的Sirtuin（SIRT）-3的降低，它已成为蛋白质家族的重要成员，该蛋白质家族恢复细胞转化和代谢。最后，我们发现慢性酒精消耗增加了心肌细胞中的麦芽素重链（MHC）比。因此，基于文献中存在的这些初步数据和信息，我们假设AHMD是由SIRT3降低引起的。随后，我们呈阳性这种变化刺激了心脏成纤维细胞向MyOFB的转化，从而增强了胶原蛋白沉积和间质纤维化，最终会损害心脏功能。为了解决该假设中隐含的问题，拟议的研究具有以下具体目的：（1）描绘酒精诱导的心脏SIRT3的减少是否与ECM营业额和AHMD的调解人意外相关。（2）确定SIRT3的体内激活是否阻止了AHMD的发展。我们的应用程序利用了心脏特异性SIRT3过表达的鼠模型的可用性，并得到了令人兴奋的初步数据的支持。我们对最先进的体内方法的关注使我们能够明确地将物理重要性分配给我们的观察。为了维持当前应用的重点，未明确提出体外研究。但是，初步数据表明，酒精还会减少SIRT3并增加培养的人类心脏成纤维细胞中的ECM产生，这表明酒精对这种细胞类型的直接影响。预期的研究结果将为SIRT3的代谢作用提供基本知识，并为AHMD的临床意义提供了第二种机械见解，从而为我们的研究重点和治疗性发育的潜力提供了广泛的转化基础。