Nitric oxide (NO), a highly versatile signaling molecule, exerts a broad range of regulatory influences in the cardiovascular system that extend from endothelial relaxation to platelet function, myocardial contractility, Ca2+ cycling, and energy metabolism. Much attention has been paid to deciphering mechanisms for such diversity in signaling, but controversy still abounds. S-nitrosylation of cysteine thiols is a major signaling pathway through which NO exerts its actions. An emerging concept of NO pathophysiology is that the interplay between NO and reactive oxygen species (ROS), the nitroso/redox balance, is an important regulator of cardiovascular homeostasis. ROS readily react with NO and limit its bioavailability and also compete with NO for binding to the same sites in effector molecules. We and others have shown that specific NO synthase (NOS) isoforms reside in precise sub-cellular organelles in cardiac myocytes and interact with oxidative enzymes in a spatially confined matter. In this grant we propose experiments that will further elucidate the significance of nitroso/redox balance in health and disease. We will take advantage of 3 newly discovered phenomena, first that NOS1 translocates in myocardial infarction, second that S-nitrosylation is tightly regulated by S- nitrosoglutathione reductase (GSNOR), which decomposes SNO bonds and last, that the well-known cardioprotective effects of NO during myocardial ischemia are mediated at least in part by S-nitrosylation of Ca+2 handling proteins.
The specific aims of this grant are to assess that 1.) NOS isoforms are in close contact with GSNOR and this close proximity allows for tight regulation of S-nitrosylation, 2.) After myocardial infarction (MI), there are selective, highly regulated interactions between xanthine oxidase and NOS1 (as opposed to NOS3) 3.) GSNOR plays a pivotal role in regulating S-nitrosylation in the heart after MI. Our work will provide an integrated view of the role of nitroso/redox balance in cardiovascular pathophysiology. The potential implications of our findings are highlighted by recent large-scale human studies where pharmacologic manipulation of oxidative and nitrosative pathways exerted salutary effects in patients with advanced heart failure.

Public Health Relevance

Myocardial infarction occurs when blood supply to the heart is inadequate and this represents the leading cause of death worldwide. In this Grant, we will explore the mechanisms through which the heart protects itself against injury. Our findings will have implications for developing new therapeutic strategies for myocardial infarction and other related common diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094849-05
Application #
8399028
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2009-02-15
Project End
2013-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2013
Total Cost
$423,946
Indirect Cost
$146,857
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Mayourian, Joshua; Ceholski, Delaine K; Gorski, Przemek A et al. (2018) Exosomal microRNA-21-5p Mediates Mesenchymal Stem Cell Paracrine Effects on Human Cardiac Tissue Contractility. Circ Res 122:933-944
Starke, Robert M; Thompson, John W; Ali, Muhammad S et al. (2018) Cigarette Smoke Initiates Oxidative Stress-Induced Cellular Phenotypic Modulation Leading to Cerebral Aneurysm Pathogenesis. Arterioscler Thromb Vasc Biol 38:610-621
White, Ian A; Sanina, Cristina; Balkan, Wayne et al. (2016) Mesenchymal Stem Cells in Cardiology. Methods Mol Biol 1416:55-87
Hatzistergos, Konstantinos E; Hare, Joshua M (2016) Murine Models Demonstrate Distinct Vasculogenic and Cardiomyogenic cKit+ Lineages in the Heart. Circ Res 118:382-7
Hatzistergos, Konstantinos E; Saur, Dieter; Seidler, Barbara et al. (2016) Stimulatory Effects of Mesenchymal Stem Cells on cKit+ Cardiac Stem Cells Are Mediated by SDF1/CXCR4 and SCF/cKit Signaling Pathways. Circ Res 119:921-30
Bagno, Luiza L; Kanashiro-Takeuchi, Rosemeire M; Suncion, Viky Y et al. (2015) Growth hormone-releasing hormone agonists reduce myocardial infarct scar in swine with subacute ischemic cardiomyopathy. J Am Heart Assoc 4:
Dulce, Raul A; Mayo, Vera; Rangel, Erika B et al. (2015) Interaction between neuronal nitric oxide synthase signaling and temperature influences sarcoplasmic reticulum calcium leak: role of nitroso-redox balance. Circ Res 116:46-55
Hatzistergos, Konstantinos E; Takeuchi, Lauro M; Saur, Dieter et al. (2015) cKit+ cardiac progenitors of neural crest origin. Proc Natl Acad Sci U S A 112:13051-6
Sanina, Cristina; Hare, Joshua M (2015) Mesenchymal Stem Cells as a Biological Drug for Heart Disease: Where Are We With Cardiac Cell-Based Therapy? Circ Res 117:229-33
Hatzistergos, Konstantinos E; Hare, Joshua M (2015) Cell Therapy: Targeting Endogenous Repair Versus Remuscularization. Circ Res 117:659-61

Showing the most recent 10 out of 64 publications