Role of Acetaldehyde in Alcoholic Cardiomyopathy

描述（由申请人提供）：长期饮酒导致酒精性心肌病的发生，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、心脏肥大以及卒中和高血压风险增加。慢性酒精中毒引起的心肌病的发生已有大量文献报道，但其发病机制尚不清楚。已经假设了几种机制，包括氧化应激、甘油三酯蓄积、脂肪酸提取改变、肌丝对Ca 2+和儿茶酚胺的反应性降低以及心脏蛋白质合成受损，然而，机制和最终毒素均未确定。特定毒素的主要候选物是乙醇，乙醇代谢的第一产物-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-收缩偶联，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）由于乙醇脱氢酶过度表达导致心脏暴露于乙醛的增加，通过增强氧化损伤和脂质过氧化作用加剧了酒精摄入后的心室功能障碍;（2）乙醛脱氢酶非特异性过度表达导致乙醛分解增加，可保护酒精性心肌病的发生;（3）乙酰丙酮酸诱导的酒精性心肌病部分是通过CYP 2 E1介导的氧化损伤介导的，并且可能通过过表达自由基清除剂如超氧化物歧化酶和金属硫蛋白来保护。最先进的细胞生物学、生理学和转基因技术将用于在转基因小鼠模型中在细胞、整个心脏和体内水平评价心脏兴奋-收缩偶联。这些研究将为乙醛在酒精性心肌病发病机制和治疗中的作用提供有益的见解。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