Cigarette Smoke and Alcohol-Induced Heart Injury

香烟烟雾和酒精引起的心脏损伤

基本信息

批准号：
7357396
负责人：
MARY O GRAY
金额：
$ 15.45万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7357396
关键词：
Acute Address Adult Age Alcohol abuse Alcohol consumption Alcoholic beverage heavy drinker Alcohols Alveolar Cell Animals Apoptosis Applications Grants Area Arrhythmia Autonomic nervous system Award Basic Science Biological Biological Markers C57BL/6 Mouse Calories Cardiac Cardiac Myocytes Cardiomyopathies Cell Survival Cessation of life Chronic Cigarette Cigarette Smoker Class Clinical Collagen Complex Condition Consensus Coronary Arteriosclerosis Cytoskeletal Modeling Deposition Development Diagnosis Diet Disease Disruption Drug abuse Early Diagnosis Energy Metabolism Enzymes Ethanol Ethanol toxicity Etiology Exposure to Fibrosis Functional disorder Gases Genes Genetic Genetic Translation Glucose Heart Heart Diseases Heart Injuries Heart failure Heavy Drinking Hepatocyte Human Hypertension Individual Infarction Inflammation Injury Institutes Ischemia Knockout Mice Learning Lipid Peroxidation Liquid substance Literature Malignant Neoplasms Measures Mediating Mediator of activation protein Metabolism Minocycline Mitochondria Mus Myocardial Myocardium NIH Program Announcements Nicotine Oxidative Stress PARP inhibition Patients Pharmaceutical Preparations Phase Physiological reperfusion Poly(ADP-ribose) Polymerases Process Protocols documentation Publishing Reactive Oxygen Species Recording of previous events Regulation Reperfusion Injury Reperfusion Therapy Research Resistance Respiratory Chain Risk Role Signal Transduction Pathway Simulate Smoke Smoking Source Structure Sudden Death Support of Research System Tars Testing Tissues Tobacco Dependence Toxic effect United States Week Xanthine Oxidase alcohol abstinence brain metabolism cigarette smoke-induced cigarette smoking cigarette smoking cohort drinking drug of abuse feeding improved inhibitor/antagonist insight interest macrophage male mouse model neutrophil non-smoker novel problem drinker programs protein degradation research study response trafficking

项目摘要

DESCRIPTION (provided by applicant): Non-ischemic cardiomyopathy, a condition in which cardiac contractile function is impaired without significant coronary artery disease, is an important cause of heart failure and sudden death but poorly understood. Alcohol abuse is considered the most common etiology of non-ischemic cardiomyopathy in the United States, but heavy drinkers rarely develop heart failure. In contrast, growing consensus in the published literature supports a primary role for cigarette smoking in the development of chronic cardiac injury. Cigarette smokers are much more likely to drink heavily than nonsmokers, and most alcoholics are dependent on nicotine. Reactive oxygen species originate from gas or tar phases of cigarette smoke, activated macrophages or neutrophils, and from endogenous sources of biological radicals including xanthine oxidase and mitochondrial respiratory chain complexes. Oxidative stress from cigarette smoke exposure causes lipid peroxidation in heart tissue, impaired energy metabolism, and reduced contractile function. Importantly, cigarette smoke stimulates robust collagen deposition in animal hearts that mimics tissue fibrosis classically associated with human cardiomyopathy. The central hypothesis of the proposed research plan is that chronic exposure to cigarette smoke triggers hyperactivation of poly(ADP-ribose) polymerase-1 (PARP-1) in cardiac myocytes, which then impairs baseline function and reduces resistance to ethanol-mediated toxicity and acute ischemia-reperfusion injury. Studies will explore a mouse model of cigarette- and alcohol-associated cardiomyopathy with three specific aims. In Specific Aim One, we plan to investigate the individual and combined effects of chronic cigarette smoke exposure and heavy ethanol intake on cardiac structure and function using adult C57BL/6 mice. In Specific Aim Two, we will test the importance of PARP-1 hyperactivation as a mediator of myocardial injury induced by cigarette smoke exposure and heavy ethanol consumption. In Specific Aim Three, we plan to investigate the individual and combined effects of cigarette smoke exposure and heavy ethanol consumption on tissue resistance to acute ischemia-reperfusion injury. Protocols generate cohorts of mice with heart disease that simulates one common form of human cardiomyopathy. We predict the project will generate novel mechanistic insights, allow us to derive biomarker profiles for diagnosis of cigarette-related heart injury, and determine the utility of PARP-1 inhibitors for treatment of cardiac disease caused by drug abuse that is difficult to approach clinically. Heart disease related to cigarette smoking and heavy drinking is an important cause of illness and death throughout the world but difficult to study carefully in patients. Research proposed in this grant application will use mice to learn how cigarette smoking and heavy drinking damage heart muscle and whether a new class of safe medications known as "PARP-1 inhibitors" help hearts recover once drug abuse has ended. Information obtained in these studies will help doctors improve the diagnosis and treatment of chronic heart disease in adult patients who smoke cigarettes and drink in excess.

描述（由申请人提供）：非缺血性心肌病（这种情况下，心脏收缩功能受损而没有明显的冠状动脉疾病，是心力衰竭和猝死的重要原因，但知识较差。酗酒被认为是美国非缺血性心肌病的最常见病因，但大量饮酒者很少出现心力衰竭。相比之下，发表的文献中日益增长的共识支持吸烟在慢性心脏损伤发展中的主要作用。吸烟者比非吸烟者更有可能大量喝酒，而且大多数酗酒者都取决于尼古丁。活性氧源于香烟烟雾，活化的巨噬细胞或中性粒细胞的气体或焦油阶段，以及包括黄嘌呤氧化酶和线粒体呼吸链复合物在内的生物自由基的内源性来源。香烟烟雾暴露的氧化应激会导致心脏组织中的脂质过氧化，能量代谢受损和收缩功能降低。重要的是，香烟烟雾刺激动物心脏中强大的胶原蛋白沉积，这些胶原蛋白模仿了与人类心肌病经典相关的组织纤维化。拟议的研究计划的核心假设是，长期暴露于香烟烟雾会引发心肌细胞中聚（ADP-核糖）聚合酶1（PARP-1）的过度激活，从而损害基线功能并降低对乙醇介导的毒性和急性介导的毒性和急性局部局部缺血性局部毒素 - 再生效果损伤。研究将探索一个具有三个特定目标的香烟和酒精相关的心肌病的小鼠模型。在特定目标中，我们计划研究使用成年C57BL/6小鼠对心脏结构和功能的慢性香烟烟雾暴露和重型乙醇摄入的个体和综合作用。在特定目标二中，我们将测试PARP-1过度激活作为烟雾烟雾和大量乙醇消耗引起的心肌损伤的介体的重要性。在特定目标三中，我们计划研究香烟烟雾暴露和大量乙醇消耗对组织抗急性缺血再灌注损伤的个体和综合作用。方案产生与心脏病的小鼠同类，该小鼠模拟了一种常见的人类心肌病。我们预测该项目将产生新颖的机械见解，使我们能够得出生物标志物概况以诊断与香烟相关的心脏损伤，并确定PARP-1抑制剂的用途，以治疗由药物滥用引起的心脏疾病，这在临床上很难接近。与吸烟和大量饮酒有关的心脏病是全世界疾病和死亡的重要原因，但在患者中很难仔细研究。本赠款申请中提出的研究将使用小鼠了解吸烟和饮酒重量如何损害心肌，以及一种新的安全药物（称为“ PARP-1抑制剂）”是否有助于一旦药物滥用结束，就可以恢复心脏。在这些研究中获得的信息将有助于医生改善吸烟和喝酒过量的成年患者的慢性心脏病的诊断和治疗。