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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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New York University
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Shekhtman, Alexander; Ramasamy, Ravichandran; Schmidt, Ann Marie (2017) Glycation & the RAGE axis: targeting signal transduction through DIAPH1. Expert Rev Proteomics 14:147-156
Senatus, Laura M; Schmidt, Ann Marie (2017) The AGE-RAGE Axis: Implications for Age-Associated Arterial Diseases. Front Genet 8:187
López-Díez, Raquel; Shen, Xiaoping; Daffu, Gurdip et al. (2017) Ager Deletion Enhances Ischemic Muscle Inflammation, Angiogenesis, and Blood Flow Recovery in Diabetic Mice. Arterioscler Thromb Vasc Biol 37:1536-1547
Schmidt, Ann Marie (2017) 2016 ATVB Plenary Lecture: Receptor for Advanced Glycation Endproducts and Implications for the Pathogenesis an Treatment of Cardiometabolic Disorders: Spotlight on the Macrophage. Arterioscler Thromb Vasc Biol 37:613-621
Manigrasso, Michaele B; Pan, Jinhong; Rai, Vivek et al. (2016) Small Molecule Inhibition of Ligand-Stimulated RAGE-DIAPH1 Signal Transduction. Sci Rep 6:22450
López-Díez, Raquel; Shekhtman, Alexander; Ramasamy, Ravichandran et al. (2016) Cellular mechanisms and consequences of glycation in atherosclerosis and obesity. Biochim Biophys Acta 1862:2244-2252
Thiagarajan, Devi; Vedantham, Srinivasan; Ananthakrishnan, Radha et al. (2016) Mechanisms of transcription factor acetylation and consequences in hearts. Biochim Biophys Acta 1862:2221-2231
Ramasamy, Ravichandran; Shekhtman, Alexander; Schmidt, Ann Marie (2016) The multiple faces of RAGE--opportunities for therapeutic intervention in aging and chronic disease. Expert Opin Ther Targets 20:431-46
Thiagarajan, Devi; Ananthakrishnan, Radha; Zhang, Jinghua et al. (2016) Aldose Reductase Acts as a Selective Derepressor of PPAR? and the Retinoic Acid Receptor. Cell Rep 15:181-96
Litwinoff, Ems; Hurtado Del Pozo, C; Ramasamy, R et al. (2015) Emerging Targets for Therapeutic Development in Diabetes and Its Complications: The RAGE Signaling Pathway. Clin Pharmacol Ther 98:135-44

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