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 iNOS produces large amounts of NO continuously, in contrast to eNOS producing smaller amounts of NO transiently, the expression of iNOS 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 iNOS can affect a variety of cardiac systems, the regulation of iNOS is of critical importance. Although the primary mechanism by which NOS2 is regulated was previously thought to be mediated by transcription, other mechanisms regulate NOS2 expression as well. Our preliminary data show that novel proteins regulate the stability of iNOS mRNA, and regulate the activity of iNOS protein. We propose to study transcriptional, post-transcriptional, and 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 molecular mechanisms by which radical production is regulated in ischemic myocardium.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL063706-01
Application #
6027003
Study Section
Pharmacology A Study Section (PHRA)
Project Start
2000-02-05
Project End
2004-01-31
Budget Start
2000-02-05
Budget End
2001-01-31
Support Year
1
Fiscal Year
2000
Total Cost
$315,900
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Harris, Tamia A; Yamakuchi, Munekazu; Kondo, Maiko et al. (2010) Ets-1 and Ets-2 regulate the expression of microRNA-126 in endothelial cells. Arterioscler Thromb Vasc Biol 30:1990-7
Lowenstein, Charles J; Cameron, Scott J (2010) High-density lipoprotein metabolism and endothelial function. Curr Opin Endocrinol Diabetes Obes 17:166-70
Ferlito, Marcella; Fulton, William B; Zauher, Mohamed A et al. (2010) VAMP-1, VAMP-2, and syntaxin-4 regulate ANP release from cardiac myocytes. J Mol Cell Cardiol 49:791-800
Cao, Wangsen; Bao, Clare; Padalko, Elizaveta et al. (2008) Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling. J Exp Med 205:1491-503
Harris, Tamia A; Yamakuchi, Munekazu; Ferlito, Marcella et al. (2008) MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci U S A 105:1516-21
Calvert, John W; Gundewar, Susheel; Yamakuchi, Munekazu et al. (2007) Inhibition of N-ethylmaleimide-sensitive factor protects against myocardial ischemia/reperfusion injury. Circ Res 101:1247-54
Yamakuchi, Munekazu; Kirkiles-Smith, Nancy C; Ferlito, Marcella et al. (2007) Antibody to human leukocyte antigen triggers endothelial exocytosis. Proc Natl Acad Sci U S A 104:1301-6
Saura, Marta; Zaragoza, Carlos; Bao, Clare et al. (2006) Stat3 mediates interleukin-6 [correction of interelukin-6] inhibition of human endothelial nitric-oxide synthase expression. J Biol Chem 281:30057-62
Ferlito, Marcella; Irani, Kaikobad; Faraday, Nauder et al. (2006) Nitric oxide inhibits exocytosis of cytolytic granules from lymphokine-activated killer cells. Proc Natl Acad Sci U S A 103:11689-94
Zaragoza, Carlos; Saura, Marta; Padalko, Elizaveta Y et al. (2006) Viral protease cleavage of inhibitor of kappaBalpha triggers host cell apoptosis. Proc Natl Acad Sci U S A 103:19051-6

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