Role of SIRT3 in alcoholic heart muscle disease

描述（由申请人提供）：酒精滥用是一个重大的公共卫生问题，会导致过早死亡、医院康复受损和多器官系统功能障碍。酒精性心肌疾病（AHMD）是持续酒精滥用的标志，近三分之一的长期酗酒者被诊断出相关的心肌病。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。尽管迄今为止对AHMD的研究主要涉及心肌本身的变化，但随着时间的推移，心脏中胶原蛋白和细胞外基质（ECM）的积累可能是导致发病的主要机制。因此，阐明长时间饮酒后调节心肌成纤维细胞转化和激活的细胞和分子机制具有临床意义。我们的长期目标是阐明AHMD的病因和发病机制。我们的初步数据表明，小鼠慢性（24周）饮酒产生心肌成纤维细胞向肌成纤维细胞（myoFBs）转分化的明确证据，这种细胞转变与胶原沉积增加（如纤维化）和心脏收缩功能障碍相关。酒精喂养小鼠的心脏也显示sirtuin (SIRT)-3的减少，SIRT -3是一种蛋白质去乙酰化酶，是调节细胞转化和代谢的蛋白质家族的重要成员。最后，我们发现长期饮酒会增加心肌细胞中肌球蛋白重链（MHC）的比例。因此，基于这些初步数据和文献中的信息，我们假设AHMD是由SIRT3减少引起的。我们假设这种变化随后刺激心肌成纤维细胞向myofb的转化，从而增强胶原沉积和间质纤维化，最终损害心功能。为了解决这一假设中隐含的问题，本研究有以下具体目的：(1)描述酒精诱导的心脏SIRT3下降是否与ECM转换有因果关系，是否是AHMD的中介；(2)确定体内激活SIRT3是否能阻止AHMD的发展。我们的应用程序利用了心脏特异性SIRT3过表达的小鼠模型的可用性，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为我们的观察分配生理重要性。为了保持当前应用的重点，没有特别提出体外研究。然而，现有的初步数据表明，酒精也会降低培养的人心脏成纤维细胞的SIRT3并增加ECM的产生，这表明酒精对这种细胞类型有直接影响。预期的研究成果将为SIRT3的代谢作用提供基础知识，并为AHMD的临床重要病理提供开创性的机制见解。，从而为我们的研究重点和治疗发展潜力提供了广泛的转化基础。

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.