Caveolae, mitochondria, and cardiac protection.

描述(申请人提供)：心肌缺血/再灌注损伤是由线粒体功能障碍所介导的，在线粒体功能障碍中，受损的线粒体在再灌流时利用氧气而不是能量来产生活性氧物种(ROS)。ROS具有破坏性的潜力。到目前为止发现的预防再灌注损伤最有益的实验干预措施是缺血预适应(IPC)，当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发生。以前的工作利用膜受体激活导致心脏保护的线性模型来评估产生IPC的单个平行通路；然而，还没有提出IPC的单一、统一的机制来解释其时间效率(即质膜与线粒体的快速耦合)和空间三维(即多个通路的同时激活)。信号转导中的一个新概念(即，在具有动态势的离散细胞间隔中组织的多蛋白质复合体的存在)为解决这一IPC的时间/空间难题提供了可能的解决方案。两种膜结构蛋白小窝蛋白-3(Cav-3)和连接蛋白43(Cx43)存在于动态的膜微环境中，为质膜富脂微区或缝隙连接微区中的多蛋白质复合体提供空间组织。关于Cav-3和Cx43在预适应心肌中的相互作用和运输，以及这些蛋白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、Cx43和线粒体之间存在密切的联系，这种联系在IPC中可能起着作用。IPC诱导的小窝蛋白和Cx43的翻译后修饰优化了小窝/线粒体的相互作用，从而减少了在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的相互作用中是必不可少的。3.小窝蛋白/Cx43的过表达可增强小窝与线粒体的相互作用，从而模拟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机制，并确定在产生预适应表型过程中协调众多信号网络的关键分子。与公共健康相关的伤害形成的心脏病是致命的，并导致死亡。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预防心脏病发作损伤的关键蛋白质，以便能够适当地设计药物。

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.