Mechanisms of Ethanol-Induced Cardiac Protection

心肌缺血前短暂暴露于低浓度乙醇(10-50 mm)可使梗塞面积减少约60% 在一个依赖于epsilon蛋白激酶C，ePKC激活的过程中。我们证明了激活 线粒体酶，乙醛脱氢酶2，ALDH2，是乙醇诱导所必需的，也是足够的 对缺血的心脏保护；一种新的ALDH2激活剂(ALDA-1)治疗模拟乙醇诱导 心脏保护。线粒体ALDH2在人类健康中的重要性也由 40%的东亚人携带ALDH2基因的失活突变的倾向增加， ALDH2*2，与氧化应激相关的各种慢性病以及由此产生的 有毒的醛积聚，包括心肌梗塞。 在下一个资助期，将实现四个目标： 目的1：研究乙醇对PKC介导的ALDH2激活的影响。诱变和 结晶学研究，将有助于确定ALDH2磷酸化如何增强乙醛催化。 目的2：确定乙醇是否对急性心肌梗死ALDH2*2小鼠有心脏保护作用 乙醇诱导的小鼠ePKC激活导致ALDH2*2的磷酸化，如果这 磷酸化可提高突变酶的催化活性 目的3：确定乙醛和4HNE修饰哪些蛋白质及其功能结果 在这些修改中。 目的4：确定通过改变底物来增强醛代谢的药理方法 对另一种ALDH酶的偏好。 总之，这些研究将阐明与细胞保护相关的动物的基本过程 野生型和非活性(ALDH2*2)ALDH2以及适度的乙醇暴露如何影响它们。建议数 研究还将提供新的工具，并测试它们作为治疗心肌缺血的应用，使用动物 模特们。 相关性(请参阅实例)： 这项拟议的研究将确定少量乙醇激活细胞的机制。 通过心脏病发作保护组织免受损伤的机制。从这项研究中获得的信息将有助于 设计更好的药物在普通人群中激活这种保护机制，并在大约40%的 东亚人，其中这种保护机制是有缺陷的。

A brief exposure to low levels of ethanol (10-50 mM) prior to cardiac ischemia reduces infarct size by ~60% in a process that is dependent on activation of epsilon protein kinase C, ePKC. We showed that activation of the mitochondrial enzyme, aldehyde dehydrogenase 2, ALDH2, is required and sufficient for ethanol-lnduced cardiac protection from ischemia; treatment with a novel activator of ALDH2 (Alda-1) mimics ethanol-lnduced cardioprotection. The importance of mitochondrial ALDH2 in human health is also suggested by the increased propensity of 40% of East Asians that carry an inactivating mutation in the ALDH2 gene, ALDH2*2, to have a variety of chronic diseases associated with oxidative stress and the resulting accumulation of toxic aldehydes, including myocardial infarction. In the next funding period, four aims will be addressed: Aim 1: Determine how ethanol-lnduced poundPKC-mediated activation of ALDH2 occurs. Mutagenesis and crystallographic studies, will help determine how ALDH2 phosphorylation enhances acetaldehyde catalysis. Aim 2: Determine if ethanol induces cardiac protection in ALDH2*2 mice from acute myocardial infarction, if ethanol-lnduced ePKC activation in these mice leads to phosphorylation of ALDH2*2 and if this phosphorylation increases the catalytic activity of the mutant enzyme Aim 3: Determine which proteins are modified by acetaldehyde and 4HNE and the functional consequence of these modifications. Aim 4: Identify pharmacological means to enhance aldehyde metabolism by changing the substrate preference of another ALDH enzyme. Together, these studies will elucidate fundamental processes associated with cytoprotection in animals with wild type and inactive (ALDH2*2) ALDH2 and how moderate ethanol exposure affects them. The proposed studies will also provide new tools and test their application as treatment for cardiac ischemia, using animal models. RELEVANCE (See Instmctions): This proposed study will identify the mechanism by which small amounts of ethanol activates a cellular mechanism that protects from tissue injury by heart attack. The information gained from this study will help design better drugs to activate this protective mechanism in the general populations and in about 40% of East Asians, in which this protective mechanism is defective.