Protection From Cardiac Reperfusion Injury by Ethanol

乙醇防止心脏再灌注损伤

• 批准号: 6881307
• 负责人: MARY O GRAY
• 金额: $ 33万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-30 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6881307
• 关键词: alcoholic beverage consumption; calcium flux; cardiac myocytes; cardiovascular pharmacology; chemoprevention; confocal scanning microscopy; cytoprotection; dosage; enzyme activity; enzyme inhibitors; ethanol; immunofluorescence technique; injury prevention; isozymes; laboratory mouse; myocardial ischemia /hypoxia; nutrition related tag; protein kinase C; protein localization; reperfusion; western blottings

DESCRIPTION (provided by applicant): Moderate alcohol intake has been shown to reduce coronary heart disease in numerous epidemiological studies. We propose that moderate ethanol consumption causes cardioprotection by increasing epsilonPKC protein expression in cardiac myocytes. To test this hypothesis, we will use multiple approaches to examine resistance of ischemia-reperfusion injury in hearts receiving ethanol in drinking water for at least 12 weeks. In addition, we will investigate the requirement for epsilonPKC function in ethanol-mediated cardioprotection using techniques routinely available in our laboratory with the following specific aims: Aim A: Examine epsilonPKC enzyme activity and subcellular localization in hearts from ethanol-fed mice and age-matched controls. We plan to identify ethanol-induced changes in epsilonPKC kinase function and distribution among subcellular compartments in adult cardiac myocytes and in left ventricular tissue from ethanol-fed mice and age-matched controls using immunofluorescence staining, confocal microscopy, immunoprecipitation, and western blotting techniques. Aim B: Determine whether acute isozyme-selective inhibition of epsilonPKC function blocks sustained ethanol-mediated cardioprotection. We will examine the effects of peptide modulators of PKC isozyme translocation and function introduced acutely into cultured adult cardiac myocytes or intact hearts on chronic ethanol-induced resistance to ischemia-reperfusion injury and PKC interactions with other signaling proteins. Aim C: Investigate the effects of moderate alcohol consumption on cardiac function and resistance to ischemia-reperfusion injury in epsilonPKC knockout mice. We will use adult cardiac myocytes and intact hearts to determine whether cardioprotection develops in epsilonPKC knockout mice in response to ethanol feeding and whether ethanol-mediated regulation of related signaling pathways is altered by the absence of epsilonPKC. One overall goal of this research is to understand the cellular mechanisms of cardioprotection mediated by chronic moderate alcohol consumption. A second goal is to identify therapeutic targets for sustained protection against coronary heart disease that do not require ethanol ingestion because of concerns regarding alcohol abuse and potential adverse effects on other organ systems in humans.

描述（申请人提供）：已显示中等酒精摄入量 在许多流行病学研究中，减少了冠心病。我们建议 适度的乙醇消耗会通过增加而导致心脏保护 心肌细胞中的Epsilonpkc蛋白表达。为了检验这一假设，我们 将使用多种方法来检查缺血再灌注的抗性 心脏受伤至少12周在饮用水中接受乙醇。在 此外，我们将研究对Epsilonpkc功能的要求 乙醇介导的心脏保护使用我们通常可用的技术 具有以下特定目的的实验室：目标A：检查epsilonpkc酶 来自乙醇喂养小鼠的心脏中的活性和亚细胞定位， 年龄匹配的控件。我们计划鉴定乙醇引起的Epsilonpkc的变化 成年人的激酶功能和亚细胞室之间的分布 心肌细胞和来自乙醇喂养的小鼠的左心室组织， 使用免疫荧光染色，共聚焦显微镜，年龄匹配的对照， 免疫沉淀和蛋白质印迹技术。 AIM B：确定急性同工酶选择性抑制Epsilonpkc 功能阻滞持续乙醇介导的心脏保护。我们将检查 PKC同工酶易位和功能的肽调节剂的影响 在 慢性乙醇引起的对缺血再灌注损伤和PKC的抗性 与其他信号蛋白的相互作用。目标C：调查 对心脏功能的中度饮酒和对 Epsilonpkc敲除小鼠的缺血 - 再灌注损伤。我们将使用成人 心肌细胞和完整的心脏确定是否心脏保护 响应于乙醇喂养以及是否是否 乙醇介导的相关信号通路的调节因 缺乏epsilonpkc。这项研究的总体目标是了解 由慢性中度酒精介导的心脏保护的细胞机制 消耗。第二个目标是确定持续的治疗目标 防止不需要乙醇摄入的冠状动脉疾病 由于担心酒精滥用和潜在的不利影响 人类的其他器官系统。