THE IMPACT OF HYPOXIA ON DEVELOPMENT AND REMODELING

心脏是缺氧引起的形态学和生理学改变的主要目标。心肌间隙连接在急性缺血事件后发生重大改变，包括受损细胞的功能和表达下降，以及组织重塑时心肌细胞中Cx43分布的重组。此外，受损肌细胞之间间隙连接的表达在缺血性损伤后似乎是有害的，允许细胞死亡从受损细胞扩散到偶联的相邻细胞（一种称为“旁观者细胞死亡”的现象）；非连接半通道打开也可能导致细胞死亡。在这个提议中要检验的一般假设是

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.