Earlier studies from our laboratory 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 wild-type mice after ischemia/reperfusion (I/R) in the isolated perfused heart or after occlusion/reperfusion of the left anterior descending (LAD) coronary artery. RAGE is expressed broadly in multiple cell types that impact on the heart's response to I/R injury, such as monocytes/macrophages, endothelial cells and cardiomyocytes. RAGE contributes to oxidative stress consequent to I/R and influences mitochondrial dysfunction that accompanies injury to the heart. In this application, we will probe the "cross- talk" between inflammatory, vascular and cardiomyocyte stresses evoked by I/R in the heart using murine models, both in the absence and presence of diabetes. Our overall hypothesis is that RAGE signaling in monocytes/macrophages, endothelial cells and cardiomyocytes is, overall, highly detrimental to the injured heart. We predict that in I/R, monocytes/macrophages produce damaging mediators that disrupt effective healing and that RAGE-dependent endothelial stress, particularly in diabetes, thwarts effective remodeling. Lastly, we predict that cardiomyocyte RAGE, highly upregulated in the murine heart after I/R, signals devastating metabolic consequences in the healing myocardium, which trigger mitochondrial dysfunction, in part through GSK-3b and apoptotic events. Two novel findings in our laboratory suggest roles for mDia-1, a member of the formin homology domain protein family and an effector of RhoGTPases, and the ROCK 1 signaling pathway in RAGE-mediated cardiovascular stress. In this application, we will probe the role of RAGE in the full context of RAGE-dependent mDia-1 and/or ROCK signaling in the heart. Only by a full understanding of potentially adaptive roles for cell-specific RAGE signaling in myocardial infarction, and the proximate signaling cascades stimulated by this receptor in I/R, will the optimal design of RAGE antagonism be achieved.

Public Health Relevance

Earlier studies from our laboratory have uncovered key roles for RAGE in myocardial infarction, as global deletion RAGE resulted in decreased myocardial necrosis, increased functional recovery and preservation of energy metabolism in hearts. The proposed studies will probe the role of RAGE in the full context of RAGE-dependent mDia-1 and/or ROCK signaling in the heart that mediates injury after myocardial infarction. Only by a full understanding of potentially adaptive roles for cell-specific RAGE signaling in myocardial infarction, and the proximate signaling cascades stimulated by this receptor in infarction, will the optimal design of RAGE antagonism be achieved.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL102022-03
Application #
8304946
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Goldberg, Suzanne H
Project Start
2010-09-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$418,275
Indirect Cost
$170,775
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Vedantham, Srinivasan; Thiagarajan, Devi; Ananthakrishnan, Radha et al. (2014) Aldose reductase drives hyperacetylation of Egr-1 in hyperglycemia and consequent upregulation of proinflammatory and prothrombotic signals. Diabetes 63:761-74