Cigarette Smoke and Alcohol-Induced Heart Injury

描述（由申请人提供）：非缺血性心肌病是一种心脏收缩功能受损但无显著冠状动脉疾病的疾病，是心力衰竭和猝死的重要原因，但了解甚少。在美国，酒精滥用被认为是非缺血性心肌病最常见的病因，但重度饮酒者很少发生心力衰竭。相反，在已发表的文献中，越来越多的共识支持吸烟在慢性心脏损伤的发展中起主要作用。吸烟者比不吸烟者更容易酗酒，而且大多数酗酒者都依赖尼古丁。活性氧来源于香烟烟雾的气相或焦油相、活化的巨噬细胞或嗜中性粒细胞，以及内源性生物自由基，包括黄嘌呤氧化酶和线粒体呼吸链复合物。香烟烟雾暴露的氧化应激导致心脏组织中的脂质过氧化，能量代谢受损，收缩功能降低。重要的是，香烟烟雾刺激动物心脏中的胶原蛋白沉积，这模拟了与人类心肌病经典相关的组织纤维化。拟议研究计划的中心假设是，长期暴露于香烟烟雾触发心肌细胞中聚（ADP-核糖）聚合酶-1（PARP-1）的过度激活，然后损害基线功能并降低对乙醇介导的毒性和急性缺血再灌注损伤的抵抗力。研究将探索香烟和酒精相关心肌病的小鼠模型，有三个具体目标。在具体目标一中，我们计划使用成年C57 BL/6小鼠研究慢性香烟烟雾暴露和大量乙醇摄入对心脏结构和功能的单独和联合影响。在具体目标2中，我们将测试PARP-1超活化作为香烟烟雾暴露和大量饮酒诱导的心肌损伤的介导物的重要性。在具体目标三中，我们计划研究香烟烟雾暴露和大量饮酒对组织抵抗急性缺血再灌注损伤的单独和联合作用。方案产生了一组患有心脏病的小鼠，模拟了一种常见的人类心肌病。我们预测该项目将产生新的机制见解，使我们能够推导出用于诊断心律失常相关心脏损伤的生物标志物谱，并确定PARP-1抑制剂用于治疗药物滥用引起的心脏病的效用，这在临床上很难接近。与吸烟和大量饮酒有关的心脏病是世界各地疾病和死亡的重要原因，但很难在患者中仔细研究。这项拨款申请中提出的研究将使用小鼠来了解吸烟和大量饮酒如何损害心肌，以及一旦药物滥用结束，一类被称为“PARP-1抑制剂”的新型安全药物是否有助于心脏恢复。从这些研究中获得的信息将有助于医生改善对吸烟和过量饮酒的成年患者的慢性心脏病的诊断和治疗。

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.