Caveolae, mitochondria, and cardiac protection.

描述（由申请人提供）：心肌缺血/再灌注损伤由线粒体功能障碍介导，其中受损的线粒体在再灌注时利用氧产生活性氧（ROS）而不是能量。ROS具有破坏性潜力。迄今为止确定的用于预防再灌注损伤的最有益的实验干预是缺血预处理（IPC），其发生在心肌在致死性缺血再灌注之前暴露于短暂的缺血再灌注事件时。先前的工作已经评估了利用导致心脏保护的膜受体激活的线性模型产生IPC的单个平行途径;然而，没有提出IPC的单一统一机制来解释其时间效率（即，质膜与线粒体的快速偶联）和空间三维性（即，同时激活多种途径）。信号转导中的一个新兴概念（即，在具有动态电位的离散细胞区室中组织的多蛋白质复合物的存在）提示了IPC的这种时间/空间难题的可能解决方案。两种膜结构蛋白，小窝蛋白-3（Cav-3）和连接蛋白43（Cx43），存在于动态膜微环境中，并为质膜的富含脂质或间隙连接微域中的多蛋白复合物提供空间组织。关于Cav-3和Cx43在预处理心肌中的相互作用和运输以及这些蛋白质的翻译后修饰对心脏保护的影响，人们知之甚少。我们的数据表明，小窝，小窝蛋白，Cx43，和线粒体的密切联系，并在IPC这种协会的可能作用。本研究的主要目的是探讨以下几个假设：1. IPC诱导的Caveolin和Cx43的翻译后修饰优化了Caveolin/线粒体的相互作用，从而减少了缺血再灌注损伤过程中产生的有害ROS。2：Caveolin和Cx43在IPC诱导的小窝与线粒体相互作用中起重要作用。3：Caveolin/Cx43过表达可增强Caveolin与线粒体的相互作用，模拟IPC。这项工作的长期目标是确定与心脏保护相关的新的信号传导机制，并确定在产生预处理表型中协调众多信号传导网络的关键分子。公共卫生相关性心脏病发作造成的伤害是致命的，会导致死亡。心脏中发现的某些蛋白质控制着损伤的程度。这项研究的目标是发现参与保护心脏病发作损伤的关键蛋白质，以便可以适当地设计药物。

DESCRIPTION (provided by applicant): Myocardial ischemia/reperfusion injury is mediated by mitochondrial dysfunction in which damaged mitochondria utilize oxygen at reperfusion for the generation of reactive oxygen species (ROS) rather than energy. ROS have destructive potential. The most beneficial experimental intervention thus far identified for preventing reperfusion injury is ischemic preconditioning (IPC), which occurs when the myocardium is exposed to brief ischemia-reperfusion events prior to lethal ischemia-reperfusion. Previous work has evaluated single parallel pathways that produce IPC utilizing a linear model of membrane receptor activation leading to cardiac protection; however, no single, unifying mechanism has been proposed for IPC to account for its temporal efficiency (i.e., rapid coupling of plasma membrane to mitochondria) and spatial 3-dimensionality (i.e., simultaneous activation of numerous pathways). An emerging idea in signal transduction (i.e., the existence of multi-protein complexes organized in discrete cellular compartments with dynamic potential) suggests a possible solution to this temporal/spatial conundrum of IPC. Two membrane structural proteins, caveolin-3 (Cav-3) and connexin43 (Cx43), exist in dynamic membrane microenvironments, and provide spatial organization to multi-protein complexes in lipid- rich or gap junctional microdomains of the plasma membrane. Little is known regarding Cav-3 and Cx43 interaction and trafficking in the preconditioned myocardium and the effect of post-translational modifications of these proteins on cardiac protection. Our data suggest a close association of caveolae, caveolin, Cx43, and mitochondria and a possible role for this association in IPC. The aims will address the following specific hypotheses: 1: The post-translational modification of caveolin and Cx43 induced by IPC optimizes caveolae/mitochondria interaction to reduce deleterious ROS generated during ischemic-reperfusion injury. 2: Caveolin and Cx43 are essential for IPC-induced interaction of caveolae and mitochondria. 3: Overexpression of caveolin/Cx43 can augment the interaction of caveolae and mitochondria to mimic IPC. The long-term goal of this work is to identify novel signaling mechanisms relevant to cardiac protection and determine the molecules critical in coordinating a multitude of signaling networks in producing a preconditioning phenotype. PUBLIC HEALTH RELEVANCE Injury form a heart attack is lethal and results in death. Certain proteins found in the heart control the degree of injury. It is the goal of this study to discover key proteins involved in protection against a heart attack injury so that drugs can be appropriately designed.