THE IMPACT OF HYPOXIA ON DEVELOPMENT AND REMODELING OF CARDIC INTERCALATED DISK

心脏是缺氧诱导的形态和生理改变的主要靶点。在急性缺血事件后，心脏缝隙连接的主要改变已经被证明，包括受损细胞中功能和表达的降低以及组织重塑时心肌细胞中Cx43分布的重组。此外，损伤的肌细胞之间的间隙连接的表达似乎是有害的缺血性损伤后，允许细胞死亡从损伤的细胞传播到耦合的邻居（称为“旁观者细胞死亡”的现象）;非连接半通道开放也可能有助于这种细胞死亡。本提案中有待检验的一般假设是， 由Cx43形成的缝隙连接是缺氧诱导的心脏损伤的靶点和介质。 本项目明确提出的研究将专门研究缺血的两个组成部分对心脏间隙连接的影响：缺氧和高碳酸血症。我们将测试三个假设：a）缺氧和高碳酸血症可通过改变Cx43及其相关蛋白的表达或改变Cx43对其结合配偶体的亲和力来影响发育中的心脏间隙连接，B）缺氧和高碳酸血症将产生间隙连接或半通道的功能变化，和c）发育中的心脏中的间隙连接可扩散在应激条件下增强的细胞损伤。这些假设主要是根据我们以前对缝隙连接对相关刺激的反应的研究制定的，在某些情况下，通过使用动物的心脏组织获得的初步数据得到证实，这些组织来自于维持100天的动物。 1-2在缺氧舱里待了几周我们希望这些研究将提供新的信息，缺血相关的应力对缝隙连接的影响。此外，由于我们对大脑和肾脏的间隙连接以及细胞pH调节的基本机制感兴趣，我们将受益于该计划中的其他项目并为之做出广泛贡献。

The heart represents a primary target of hypoxia-induced morphological and physiological alterations. Major alterations in cardiac gap junctions have been demonstrated following acute ischemic events, including decreased function and expression in damaged cells as well as reorganization of Cx43 distribution in the cardiac muscle cells as the tissue remodels. Moreover, expression of gap junctions between injured myocytes appears to be deleterious following ischemic injury, allowing spread of cell death from the injured cell to coupled neighbors (a phenomenon termed "bystander cell death"); nonjunctional hemichannel opening may also contribute to this cell death. The general hypotheses to be tested in this proposal are that gap junctions formed by Cx43 are both targets and mediators of hypoxia-induced cardiac injury. The studies that are explicitly proposed for this Project will specifically study effects on cardiac gap junctions of two components of ischemia: hypoxia and hypercapnia. We will test three hypotheses: a) that hypoxia and hypercapnia may affect developing cardiac gap junctions through altered expression of Cx43 and its associated proteins or altered affinity of Cx43 for its binding partners, b) that hypoxia and hypercapnia will produce functional changes in gap junctions or hemichannels, and c) that gap junctions in developing heart can spread cell injury that is enhanced under stressful conditions. These hypotheses are formulated primarily on the basis of our previous studies of responses of gap junctions to related stimuli, substantiated in some cases by preliminary data obtained using cardiac tissue from animals maintained for 1-2 weeks in the hypoxia chambers. We expect that these studies will provide new information regarding effects on gap junctions of ischemia-related stresses. In addition, we will both benefit from and contribute broadly to the other Projects in the Program, due to our interest in gap junctions in brain and kidney and in the basic mechanisms of cellular pH regulation.