Nitric oxide (NO) plays a major role in inflammatory diseases of the myocardium. NO is produced during viral myocarditis, transplant rejection, and post-ischemic inflammation in the heart. The major source of NO in the heart is normally endothelial nitric oxide synthase (eNOS or NOS3), which is present in endothelial cells, cardiac myocytes, and platelets. However, cytokines produced during ischemia or inflammation of the heart can induce expression of the inducible NOS (iNOS or NOS2) in a variety of cells, including cardiac myocytes and macrophages. Since NOS2 produces large amounts of NO continuously, in contrast to eNOS producing smaller amounts of NO transiently, the expression of NOS2 changes the concentration and location of NO in the heart. Alterations in NO production can have profound implications for cardiac physiology, since NO has a variety of effects upon the heart, including relaxation of coronary arterial smooth muscle, inhibition of cardiac myocyte contractility, reduction of platelet and leukocyte adhesion to the coronary artery wall, inhibition of glycolysis and oxidative phosphorylation, and regulation of apoptotic pathways. Because NO derived from NOS2 can affect a diversity of cardiac systems, the regulation of NOS2 is of critical importance. Although transcription was thought to be the primary mechanism by which NOS2 is regulated, other mechanisms regulate NOS2 expression as well. Our preliminary data show that novel proteins regulate the stability of NOS2 mRNA and regulate the activity of NOS2 protein. We propose to study transcriptional, post-transcriptional, and also post-translational mechanisms of NOS2 regulation. We then will examine the physiological relevance of NOS2 regulation in a post-ischemic model of myocardial infarction. These studies will characterize novel mechanisms which regulate radical production in ischemic myocardium.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL065608-03
Application #
6654181
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
2002-08-01
Project End
2003-07-31
Budget Start
Budget End
Support Year
3
Fiscal Year
2002
Total Cost
$297,097
Indirect Cost
Name
Johns Hopkins University
Department
Type
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Velayutham, Murugesan; Hemann, Craig F; Cardounel, Arturo J et al. (2016) Sulfite Oxidase Activity of Cytochrome c: Role of Hydrogen Peroxide. Biochem Biophys Rep 5:96-104
Xie, Lin; Talukder, M A Hassan; Sun, Jian et al. (2015) Liposomal tetrahydrobiopterin preserves eNOS coupling in the post-ischemic heart conferring in vivo cardioprotection. J Mol Cell Cardiol 86:14-22
Long 3rd, Victor P; Bonilla, Ingrid M; Vargas-Pinto, Pedro et al. (2015) Heart failure duration progressively modulates the arrhythmia substrate through structural and electrical remodeling. Life Sci 123:61-71
Reyes, Levy A; Boslett, James; Varadharaj, Saradhadevi et al. (2015) Depletion of NADP(H) due to CD38 activation triggers endothelial dysfunction in the postischemic heart. Proc Natl Acad Sci U S A 112:11648-53
Joddar, Binata; Firstenberg, Michael S; Reen, Rashmeet K et al. (2015) Arterial levels of oxygen stimulate intimal hyperplasia in human saphenous veins via a ROS-dependent mechanism. PLoS One 10:e0120301
Zheng, Xiaoxu; Zu, Lingyun; Becker, Lewis et al. (2014) Ischemic preconditioning inhibits mitochondrial permeability transition pore opening through the PTEN/PDE4 signaling pathway. Cardiology 129:163-73
Moldovan, Nicanor I; Anghelina, Mirela; Varadharaj, Saradhadevi et al. (2014) Reoxygenation-derived toxic reactive oxygen/nitrogen species modulate the contribution of bone marrow progenitor cells to remodeling after myocardial infarction. J Am Heart Assoc 3:e000471
Huang, Jie; Huffman, Jennifer E; Yamakuchi, Munekazu et al. (2014) Genome-wide association study for circulating tissue plasminogen activator levels and functional follow-up implicates endothelial STXBP5 and STX2. Arterioscler Thromb Vasc Biol 34:1093-101
Chen, Yeong-Renn; Zweier, Jay L (2014) Cardiac mitochondria and reactive oxygen species generation. Circ Res 114:524-37
Tong, Jianjing; Zweier, Joseph R; Huskey, Rachael L et al. (2014) Effect of temperature, pH and heme ligands on the reduction of Cygb(Fe(3+)) by ascorbate. Arch Biochem Biophys 554:1-5

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