Role of Acetaldehyde in Alcoholic Cardiomyopathy

乙醛在酒精性心肌病中的作用

基本信息

批准号：
7214167
负责人：
JUN REN
金额：
$ 20.82万
依托单位：
UNIVERSITY OF WYOMING
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2009-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7214167
关键词：
ALDH3 Acetaldehyde Actins Address Affect Alcohol consumption Alcohol dehydrogenase Alcoholic Cardiomyopathy Alcoholism Alcohols Aldehyde dehydrogenase (NAD+)Animals Antioxidants Apoptosis Arts Blood Body Burden Breeding Butylated Hydroxytoluene CYP2E1 gene Cardiac Cardiac Myocytes Cardiac Output Cardiomyopathies Catecholamines Cell physiology Cellular biology Chickens Chronic Chronic stress Control Animal Coupling Cytochrome P-450 CYP2E1 Data Defect Development EFRAC Echocardiography Elevation Esters Ethanol Ethanol Metabolism Evaluation Exposure to Fatty Acids Free Radical Scavengers Free Radicals Functional disorder Generations Genetic Goals Heart Heart Contractilities Heart Hypertrophy Hypertension In Vitro Isoenzymes Laboratories Left Lipid Peroxidation Lipids Manganese Superoxide Dismutase Mediating Metallothionein Microfilaments Microscopic Mitochondria Molecular Monitor Morphology Mus Myocardial dysfunction Myocardium Myopathy Numbers Organ Oxidative Stress Oxygen Pathogenesis Personal Satisfaction Physiology Play Prevention Production Protein Biosynthesis Protein Overexpression Proteins Respiration Risk Role Running Severities Speed Stroke Superoxide Dismutase Techniques Testing Therapeutic Toxin Transgenes Transgenic Mice Transgenic Organisms Triglycerides Ventricular Ventricular Dysfunction aldehyde dehydrogenases base catalase chronic alcohol ingestion in vivo inhibitor/antagonist insight mouse model prevent promoter

项目摘要

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

描述（申请人提供）：长期饮酒会导致酒精性心肌病，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、心脏肥大以及中风和高血压的风险增加。尽管心肌病的发病机制仍不清楚，但慢性酒精中毒引起的心肌病的发生已有充分记录。已经假设了几种机制，包括氧化应激、甘油三酯的积累、脂肪酸提取的改变、肌丝对 Ca2+ 和儿茶酚胺的反应性降低以及心脏蛋白质合成受损，然而，无论是机制还是最终的毒素都尚未确定。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。我们的实验室和其他实验室提供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）由于乙醇脱氢酶过度表达，心脏对乙醛的暴露增加，通过增强氧化损伤和脂质过氧化，加剧摄入酒精后的心室功能障碍； (2) 乙醛分解增加和乙醛脱氢酶非特异性过度表达可以保护酒精性心肌病的发展； (3)乙醛诱导的酒精性心肌病部分是通过CYP2E1介导的氧化损伤介导的，并且可能通过自由基清除剂（例如超氧化物歧化酶和金属硫蛋白）的过度表达来保护。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中细胞、整个心脏和体内水平的心脏兴奋-收缩耦合。这些研究将为酒精性心肌病的发病机制和治疗中乙醛在酒精性心肌病发展中的作用提供有用的见解。我们的长期目标是建立乙醛在酒精性心肌病发生发展过程中的毒性机制，以便优化预防和治疗