Mechanisms of Protection against Cardiac Ischemia-Reperfusion Injury

冠状动脉狭窄，导致心脏灌注受损、缺血和心肌梗死的风险， 是美国人口发病率和死亡率的主要原因。目前有极大的兴趣 了解脑缺血和脑梗塞的内源性反应。这些研究可能会导致 开发新的治疗策略，通过促进适应性反应或通过 防止不良适应反应。缺血的特征是缺氧(缺氧)、代谢 底物、细胞因子/生存因子，以及有毒代谢物的积累。尽管复杂 缺血的病理生理学，缺氧本身就足以刺激诱导各种适应性反应 对缺血再灌注损伤有保护作用。这些反应的一个重要中介是低氧诱导的。 因子1(HIF-1)，一种转录因子，调节数百个基因的表达，以响应 细胞氧合的变化。已知的HIF-1靶基因包括编码促红细胞生成素的基因 促红细胞生成素(EPO)和血管内皮生长因子(VEGF)，通过刺激促进组织的氧气输送 分别生产红血球和血管。HIF-1靶基因也编码生存 胰岛素样生长因子2、促红细胞生成素和血管内皮生长因子等可阻断细胞凋亡信号的因子 由缺血引起的。HIF-1还控制葡萄糖转运蛋白和糖酵解酶的表达，这是 是厌氧生产三磷酸腺苷所必需的。在这个提案中，我们将研究HIF-1和蛋白质的作用 促红细胞生成素等HIF-1靶基因编码对心肌缺血再灌注损伤的保护作用 受伤。目的1研究促红细胞生成素保护心脏免受缺血损伤的机制 和再灌流。目的2研究缺氧诱导因子-1在心肌缺血适应性反应中的作用 和再灌流。目标3将研究骨髓来源的募集的机制和后果 基质细胞转移到缺血心脏，

Coronary artery stenosis, resulting in impaired cardiac perfusion, ischemia, and the risk of myocardial infarction, is a major cause of morbidity and mortality in the U. S. population. There is currently tremendous interest in understanding the endogenous responses to ischemia and infarction. These studies may lead to the development of novel therapeutic strategies that protect the heart by promoting adaptive responses or by preventing maladaptive responses. Ischemia is characterized by deprivation of oxygen (hypoxia), metabolic substrates, and cytokines/survival factors, as well as accumulation of toxic metabolites. Despite the complex pathophysiology of ischemia, hypoxia alone is a sufficient stimulus to induce a variety of adaptive responses that protect against ischemia-reperfusion injury. An important mediator of these responses is hypoxia-inducible factor 1 (HIF-1), a transcription factor that regulates the expression of hundreds of genes in response to changes in cellular oxygenation. Among the known HIF-1 target genes are those encoding erythropoietin (EPO) and vascular endothelial growth factor (VEGF), which promote oxygen delivery to tissues by stimulating the production of red blood cells and blood vessels, respectively. HIF-1 target genes also encode survival factors, such as insulin-like growth factor 2 as well as EPO and VEGF, which can block apoptotic signaling induced by ischemia. HIF-1 also controls the expression of glucose transporters and glycolytic enzymes, which are required for anaerobic ATP production. In this proposal, we will investigate the role of HIF-1 and of proteins encoded by HIF-1 target genes, such as EPO, in promoting protection against cardiac ischemia-reperfusion injury. Aim 1 will investigate the mechanisms by which EPO protects the heart from injury following ischemia and reperfusion. Aim 2 will investigate the role of HIF-1 in mediating adaptive responses to cardiac ischemia and reperfusion. Aim 3 will investigate the mechanisms and consequences of the recruitment of bone marrowderived stromal cells to the ischemic heart,