Mechanisms of Protection against Cardiac Ischemia-Reperfusion Injury

Johns Hopkins University, Baltimore MD

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Abstract

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