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， 是美国发病率和死亡率的主要原因。S.人口目前，人们对 了解缺血和梗死的内源性反应。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 防止适应不良反应。缺血的特征在于缺氧（缺氧）、代谢性缺氧、缺血性脑血管病（缺血性脑血管病）。 底物和细胞因子/存活因子，以及毒性代谢物的积累。在复杂的 在缺血的病理生理学中，单独的缺氧是足以诱导各种适应性反应的刺激 可以防止缺血再灌注损伤。这些反应的一个重要介质是缺氧诱导的 因子1（HIF-1），一种调节数百个基因表达的转录因子， 细胞氧合的变化。在已知的HIF-1靶基因中，有编码促红细胞生成素的基因 (EPO)和血管内皮生长因子（VEGF），其通过刺激血管内皮生长因子（VEGF）的活性来促进氧向组织的输送。 红细胞和血管的产生。HIF-1靶基因也编码存活 因子，如胰岛素样生长因子2以及EPO和VEGF，其可以阻断凋亡信号传导 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， 是厌氧ATP生产所必需的。在本研究中，我们将研究HIF-1和蛋白质在肿瘤细胞中的作用。 由HIF-1靶基因编码，如EPO，促进对心脏缺血-再灌注的保护 损伤目的1探讨促红细胞生成素（EPO）对缺血性心脏损伤的保护机制 再灌注。目的2探讨HIF-1在心肌缺血适应性反应中的作用 再灌注。目的3：探讨骨髓源性细胞募集的机制和后果 移植到缺血的心脏，

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,