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.
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.
|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|
|Figueiredo-Freitas, Cícero; Dulce, Raul A; Foster, Matthew W et al. (2015) S-Nitrosylation of Sarcomeric Proteins Depresses Myofilament Ca2+)Sensitivity in Intact Cardiomyocytes. Antioxid Redox Signal 23:1017-34|
|Hatzistergos, Konstantinos E; Paulino, Ellena C; Dulce, Raul A et al. (2015) S-Nitrosoglutathione Reductase Deficiency Enhances the Proliferative Expansion of Adult Heart Progenitors and Myocytes Post Myocardial Infarction. J Am Heart Assoc 4:|
|Karantalis, Vasileios; Hare, Joshua M (2015) Use of mesenchymal stem cells for therapy of cardiac disease. Circ Res 116:1413-30|
|Hare, Joshua M; Sanina, Cristina (2015) Bone Marrow Mononuclear Cell Therapy and Granulocyte Colony-Stimulating Factor for Acute Myocardial Infarction: Is it Time to Reconsider? J Am Coll Cardiol 65:2383-7|
|Karantalis, Vasileios; Schulman, Ivonne Hernandez; Balkan, Wayne et al. (2015) Allogeneic cell therapy: a new paradigm in therapeutics. Circ Res 116:12-5|
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