Myocardial infarction is a major contributor to morbidity and mortality and is exacerbated by diabetes. However, the mechanisms underlying this increased susceptibility to cardiac injury in diabetic patients are not well understood. Previous studies by our laboratory have revealed a central role for the receptor for advanced glycation end-products (RAGE) in myocardial infarction, as global deletion of RAGE resulted in decreased myocardial necrosis, increased functional recovery and preservation of ATP compared to wild-type littermates 48 hours after ischemia/reperfusion (I/R). RAGE is expressed in multiple cell types that impact the myocardial response to I/R injury, such as monocytes/macrophages, endothelial cells, and cardiomyocytes. We have uncovered that RAGE contributes to oxidative stress consequent to I/R and influences mitochondrial dysfunction that accompanies injury to the heart. Ligands for RAGE are increased under diabetic conditions and after I/R, leading to increased downstream signaling. Our laboratory has discovered that the RAGE cytoplasmic domain interacts with diaphanous-1 (mDia-1), a member of the formin family, and an effector of Rho GTPases. The overall goal of the proposed research is to investigate RAGE/mDia1 signaling in cardiomyocytes in response to I/R injury. We predict that cardiomyocyte-specific RAGE and mDia, both highly upregulated in the murine heart after I/R, signal devastating metabolic consequences in the myocardium, which trigger mitochondrial dysfunction. Ideally, this research will translate into an improved prognosis for diabetic patients who have undergone myocardial infarction. To meet this goal, we will use the left anterior descending coronary artery ligation model of I/R in strains of diabetic and non- diabetic mice with genetic variations in RAGE and mDia1 expression. We will assess differences in I/R-induced left ventricular dysfunction due to genetic strain by echocardiography. Additionally, we will perform more targeted studies of hypoxia/reoxygenation in cardiomyocytes isolated from wild type and transgenic mice. We will use the ex vivo perfused heart model to assess mitochondrial function. My proposed studies will provide information to guide future efforts for the treatment of diabetic patients who have undergone myocardial infarction and prevent the development of further complications. In addition, this project will help me accomplish my training goals, which are to 1) characterize and use transgenic mice to test the hypothesis that RAGE/mDia1 signaling lead to devastating metabolic consequences in the myocardium, 2) use primary cardiomyocytes to address the mechanisms involved, 3) employ the ex vivo perfused heart model of ischemia/reperfusion to address the hypothesis, and 4) master the use of physiologically relevant models to assess I/R injury. The successful completion of this research will increase my knowledge, skill set, and potential to achieve my ultimate goal of becoming an independent researcher in cardiovascular disease.

Public Health Relevance

The high rate of mortality and morbidity in diabetic patients can be partially attributed to an increased susceptibility to injury in response to myocardial infarction;however, the mechanisms behind this phenomenon are unknown. This project will investigate the signaling mechanisms of the receptor for advanced glycation end products, which has been identified as a central mediator of the myocardial response to ischemia/reperfusion injury. The successful completion of this project will identify potential therapeutic targets for the treatment of diabetic patients who have undergone myocardial infarction while simultaneously preparing me for a future career goal of being an independent researcher in the field of cardiovascular disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F10A-S (20))
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Meadows, Tawanna
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New York University
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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