Myocardial infarction and its consequences are a leading cause of morbidity and mortality. Earlier studies by us have uncovered key roles for RAGE in myocardial infarction, as global deletion RAGE resulted in decreased myocardial necrosis, increased functional recovery and preservation of ATP compared to wildtype littermates 48 hours after ischemia/reperfusion (l/R). Our studies have uncovered that RAGE contributes to oxidative stress consequent to l/R and influences mitochondrial dysfunction that accompanies injury to the heart. A thorough approach to understanding the basic mechanisms underlying the effects of global RAGE deletion requires cell-specific dissection of the precipitating pathways of injury. Novel findings from our group during the past year enhance the direction of the proposed studies in this application: the RAGE cytoplasmic domain interacts with diaphanous-1 (mDia-1), a member of the formin homology domain protein family and an effector of Rho GTPases. mDial is essential for RAGE ligand-mediated cellular migration and activation of cdc42/rac-1. In this project, we will probe the signaling mechanisms in cardiomyocyte stresses evoked by l/R in the heart using murine models, both in the absence and presence of diabetes. We hypothesize that cardiomyocyte RAGE and mDial, highly upregulated in the murine heart after l/R, signals devastating metabolic consequences in the myocardium, which trigger mitochondrial dysfunction, in part through GSK-3n, ROCK and apoptotic events. These concepts will be explored in depth using novel RAGE and mDial floxed mice in murine models of l/R in the heart. Project 3 is integrally linked within the Program and will study cell-specific RAGE and mDia-1 signaling in myocardial infarction. Project 3 shares findings from Affymetrix gene array studies with Projects 1&2 to create integrated pathways by which RAGE signaling regulates cardiovascular stress. Project 3 uses all three Cores of the Program during all five years.
In subjects with diabetes, the incidence and severity of myocardial infarction and heart failure is increased. This application focuses on the Receptor for Advanced Glycation Endproducts (RAGE) and its biology in myocardial and the remodeling response. Only by a full understanding of RAGE's role in this setting will novel cardioprotective strategies in myocardial infarction be identified.
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