Role of Acetaldehyde in Alcoholic Cardiomyopathy

描述（由申请人提供）：慢性酒精摄入导致酒精性心肌病的发展，表现为左心室扩张，左心室收缩力受损，射血分数和心输出量降低，心脏肥厚，卒中和高血压风险增加。慢性酒精中毒引起心肌病的发生已有文献记载，但其发病机制尚不清楚。几种机制被假设包括氧化应激，甘油三酯积累，脂肪酸提取改变，肌丝对Ca2+和儿茶酚胺的反应性降低，心脏蛋白质合成受损，然而，无论是机制还是最终的毒素都没有确定。特定毒素的主要候选物是乙醇，乙醇代谢的第一个产物-乙醛和脂肪酸乙酯。来自我们实验室和其他实验室的令人信服的证据表明，乙醛直接损害心脏兴奋-收缩耦合，促进氧化损伤，并加剧酒精性心肌病的严重程度。我们的中心假设是：(1)由于酒精脱氢酶的过度表达，心脏暴露于乙醛的水平升高，通过增强氧化损伤和脂质过氧化，加剧了酒精摄入后的心室功能障碍；(2)醛脱氢酶非特异性过表达导致乙醛分解增加可保护酒精性心肌病的发生；(3)乙醛诱导的酒精性心肌病部分通过cyp2e1介导的氧化损伤介导，并可能受到自由基清除剂如超氧化物歧化酶和金属硫蛋白的过度表达的保护。最先进的细胞生物学、生理学和转基因技术将用于评估转基因小鼠模型在细胞、全心和体内水平上的心脏兴奋-收缩耦合。这些研究将提供有用的见解乙醛在酒精性心肌病的发病机制和治疗的酒精性心肌病的发展中的作用。我们的长期目标是建立乙醛在酒精性心肌病发展中的毒性机制，从而优化预防和治疗

DESCRIPTION (provided by applicant): Chronic alcohol ingestion leads to the development of alcoholic cardiomyopathy, which is manifested by left ventricular dilation, impaired left ventricular contractility, reduced ejection fraction and cardiac output, cardiac hypertrophy and enhanced risk of stroke and hypertension. The occurrence of the cardiomyopathy under chronic alcoholism has been well documented, although the pathogenesis of the myopathy is still unclear. Several mechanisms have been postulated including oxidative stress, accumulation of triglycerides, altered fatty acid extraction, decreased myofilament responsiveness to Ca2+ and catecholamines, and impaired cardiac protein synthesis, however, neither the mechanism nor the ultimate toxin has been established. Principle candidates for the specific toxins are ethanol, the first product of the ethanol metabolism - acetaldehyde and fatty acid ethyl esters. Compelling evidence from our laboratories and others has suggested that acetaldehyde directly impairs cardiac excitation-contraction coupling, promotes oxidative damage, and exacerbates the severity of alcoholic cardiomyopathy. Our central hypothesis is that (1) elevated exposure of heart to acetaldehyde due to overexpression of alcohol dehydrogenase exacerbates ventricular dysfunction following alcohol ingestion via enhanced oxidative damage and lipid peroxidation; (2) development of alcoholic cardiomyopathy can be protected by increased acetaldehyde breakdown with non-specific over-expression of aldehyde dehydrogenase; (3) acetaldehyde-induced alcoholic cardiomyopathy is mediated in part through CYP2E1-mediated oxidative damage and may be protected by overexpression of free radical scavengers such as superoxide dismutase and metallothionein. State-of-the-arts cell biology, physiology and transgenic techniques will be used to evaluate cardiac excitation-contraction coupling at cellular, whole heart and in vivo levels in transgenic mice models. These studies will provide useful insights into the role of acetaldehyde in the development of alcoholic cardiomyopathy in the pathogenesis and therapeutics of alcoholic cardiomyopathy. Our long-term goal is to establish the toxic mechanism of acetaldehyde in the development of alcoholic cardiomyopathy so that prevention and treatment can be optimized