Role of Acetaldehyde in Alcoholic Cardiomyopathy

乙醛在酒精性心肌病中的作用

• 批准号: 7380098
• 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
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7380098
• 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

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（由申请人提供）：慢性酒精摄入导致酒精性心肌病的发展，这表现为左心室扩张，左心室收缩障碍受损，射血分数和心脏肥大，心脏肥大以及卒中风险增强和高血压。尽管肌病的发病机理仍不清楚，但在慢性酒精中毒下的心肌病的发生已得到充分证明。已经假设了几种机制，包括氧化应激，甘油三酸酯的积累，脂肪酸提取改变，肌细丝对Ca2+和儿茶酚胺的反应性降低以及心脏蛋白质合成受损，但是，机制和最终毒素均未确定。特定毒素的主要候选物是乙醇，乙醇是乙醇代谢的第一产物 - 乙醛和脂肪酸乙基酯。我们实验室和其他人的令人信服的证据表明，乙醛直接损害心脏激发耦合，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，通过增强氧化损伤和脂质过氧化，心脏升高到乙醛中的暴露升高。 （2）可以通过乙醛分解增加，并通过醛脱氢酶的非特异性过表达来保护酒精性心肌病的发展； （3）乙醛诱导的酒精性心肌病是通过CYP2E1介导的氧化损伤的一部分介导的，可以通过过表达自由基清除剂（例如超氧化物歧化酶和金属硫蛋白）的过表达来保护。最先进的细胞生物学，生理和转基因技术将用于评估转基因小鼠模型中细胞，全心和体内水平的心脏激发 - 收缩耦合。这些研究将为乙醛在酒精性心肌病的发展中的作用中提供有用的见解。我们的长期目标是在酒精性心肌病的发展中建立乙醛的有毒机制，以便可以优化预防和治疗

项目成果

AMP-dependent kinase and autophagic flux are involved in aldehyde dehydrogenase-2-induced protection against cardiac toxicity of ethanol.

• DOI: 10.1016/j.freeradbiomed.2011.08.002
• 发表时间: 2011-11-01
• 期刊: FREE RADICAL BIOLOGY AND MEDICINE
• 影响因子: 7.4
• 作者: Ge, Wei;Guo, Rui;Ren, Jun
• 通讯作者: Ren, Jun

mTOR-STAT3-notch signalling contributes to ALDH2-induced protection against cardiac contractile dysfunction and autophagy under alcoholism.

• DOI: 10.1111/j.1582-4934.2011.01347.x
• 发表时间: 2012-03
• 期刊: Journal of cellular and molecular medicine
• 影响因子: 5.3
• 作者: Ge W;Ren J
• 通讯作者: Ren J

Involvement of AMPK in alcohol dehydrogenase accentuated myocardial dysfunction following acute ethanol challenge in mice.

• DOI: 10.1371/journal.pone.0011268
• 发表时间: 2010-06-23
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Guo R;Scott GI;Ren J
• 通讯作者: Ren J

Aldehyde dehydrogenase 2 knockout accentuates ethanol-induced cardiac depression: role of protein phosphatases.

• DOI: 10.1016/j.yjmcc.2010.03.017
• 发表时间: 2010-08
• 期刊: Journal of molecular and cellular cardiology
• 影响因子: 5
• 作者: Ma H;Yu L;Byra EA;Hu N;Kitagawa K;Nakayama KI;Kawamoto T;Ren J
• 通讯作者: Ren J

Inhibition of CYP2E1 attenuates chronic alcohol intake-induced myocardial contractile dysfunction and apoptosis.

CYP2E1 的抑制可减轻慢性酒精摄入引起的心肌收缩功能障碍和细胞凋亡。

• DOI: 10.1016/j.bbadis.2012.08.014
• 发表时间: 2013-01
• 期刊: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
• 影响因子: 6.2
• 作者: Zhang, Rong-Huai;Gao, Jian-Yuan;Guo, Hai-Tao;Scott, Glenda I.;Eason, Anna R.;Wang, Xiao-Ming;Ren, Jun
• 通讯作者: Ren, Jun