Reperfusion induced myocyte cell death is a problem spanning all therapeutic approaches to the treatment of acute ischemic heart disease. While much research has been no clear understanding of the underlying causal factors associated with cell death during early versus late phase of reperfusion following an ischemic episode. Two major distinct types of cell death in myocytes, necrosis and apoptosis, have been linked with ischemia and reperfusion. We recently found that necrotic cell death develops from early to late phase of reperfusion with a peak at 24 h followed by a delayed apoptotic cell death in perinecrotic myocardium after 48 h of reperfusion. We hypothesize that necrotic cell death is responsible for early reperfusion induced myocardial injury and the progression of apoptotic cell death causes extension of infarction during the late phase of reperfusion. There are three specific aims as follows: 1) Examine the role of necrotic and apoptotic cell death in determining final infarct extension, post ischemic myocardial blood flow defect, vascular endothelial and contractile dysfunction during early and late phases of reperfusion, 2) Determine the migration and localization of inflammatory blood cells neutrophil, monocyte/macrophage and mast cell, expression of adhesion molecules in inflammatory cells, vascular endothelium and myocyte, and regulation of apoptotic genes as well as fibroblast proliferation during early and late phases of reperfusion, 3) Explore the """"""""window of opportunity"""""""" in salvaging myocyte cell death by using a number of potential mechanical and pharmacologic interventions as probes including depletion of inflammatory cells (neutrophil and macrophage), antiadhesion molecules (CD11/CD18 and ICAM:1 or PECAM1), and antiapoptotic activity to determine whether the opportunity offered by the modulation of myocyte cell death will finally translate into new treatment approaches for ischemia/reperfusion induced injury. It is expected that this work will provide new directions in research investigating mechanisms underlying myocyte cell death during reperfusion and thus help in therapeutic decision making.
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