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 inunderstanding the endogenous responses to ischemia and infarction. These studies may lead to thedevelopment of novel therapeutic strategies that protect the heart by promoting adaptive responses or bypreventing maladaptive responses. Ischemia is characterized by deprivation of oxygen (hypoxia), metabolicsubstrates, and cytokines/survival factors, as well as accumulation of toxic metabolites. Despite the complexpathophysiology of ischemia, hypoxia alone is a sufficient stimulus to induce a variety of adaptive responsesthat protect against ischemia-reperfusion injury. An important mediator of these responses is hypoxia-induciblefactor 1 (HIF-1), a transcription factor that regulates the expression of hundreds of genes in response tochanges 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 stimulatingthe production of red blood cells and blood vessels, respectively. HIF-1 target genes also encode survivalfactors, such as insulin-like growth factor 2 as well as EPO and VEGF, which can block apoptotic signalinginduced by ischemia. HIF-1 also controls the expression of glucose transporters and glycolytic enzymes, whichare required for anaerobic ATP production. In this proposal, we will investigate the role of HIF-1 and of proteinsencoded by HIF-1 target genes, such as EPO, in promoting protection against cardiac ischemia-reperfusioninjury.
Aim 1 will investigate the mechanisms by which EPO protects the heart from injury following ischemiaand reperfusion.
Aim 2 will investigate the role of HIF-1 in mediating adaptive responses to cardiac ischemiaand reperfusion.
Aim 3 will investigate the mechanisms and consequences of the recruitment of bone marrowderivedstromal cells to the ischemic heart,
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