Nitroso/redox balance in myocardial infarction

Project: Research project

Description

DESCRIPTION (provided by applicant): 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.
StatusFinished
Effective start/end date2/15/0912/31/13

Funding

  • National Institutes of Health: $423,946.00
  • National Institutes of Health: $445,322.00
  • National Institutes of Health: $449,820.00
  • National Institutes of Health: $459,000.00
  • National Institutes of Health: $445,322.00

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Oxidation-Reduction
Nitric Oxide
Myocardial Infarction
Organized Financing
glutathione-independent formaldehyde dehydrogenase
Nitric Oxide Synthase
Reactive Oxygen Species
Protein Isoforms
Xanthine Oxidase
Cardiovascular System
Sulfhydryl Compounds
Cardiac Myocytes
Organelles
Energy Metabolism
Biological Availability
Myocardial Ischemia
Cysteine
Homeostasis
Blood Platelets
Heart Failure

ASJC

  • Medicine(all)