Abstract

The role of inducible nitric oxide synthase (iNOS) in the biochemistry and pathobiology of cardiac allograft rejection will be investigated. Previous work demonstrated that iNOS mRNA and enzyme activity was induced in macrophages infiltrating the myocardium and in cardiac myocytes during cardiac allograft rejection. The major hypothesis to be tested in this proposal is that NO in the rejecting graft augments myocardial inflammation and contributes to death of cardiac myocytes. These studies will address the following specific aims: 1) whether relatively selective iNOS inhibition will reduce myocardial inflammation and myocyte death in allografts, 2) whether inflammation and monocyte death is ameliorated by transplanting normal mouse hearts into mice genetically unable to induce iNOS (IRF-1 null mice), 3) if induction of cyclooxygenase-2 augments myocardial inflammation and myocyte necrosis, and if cyclooxygenase and iNOS inhibition ameliorate rejection. In addition, 4) a new strategy employing an arginine transport inhibitor which decreases NO synthesis will be examined for its effect on allograft rejection. Finally, 5) the mechanism by which NO produces death of cardiac myocytes will be investigated in detail. The results of the proposed experiments may provide new information concerning the role of iNOS in the pathobiology of cardiac rejection and suggest new therapies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL054764-02
Application #
2415666
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1996-05-01
Project End
1999-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032

  Publications

Liu, Yulin; Son, Ni Huiping; Szabolcs, Matthias J et al. (2004) Effects of inhibition of poly(adenosine diphosphate-ribose) synthase on acute cardiac allograft rejection. Transplantation 78:668-74
Ramasamy, Ravichandran; Hwang, Yuying C; Liu, Yulin et al. (2004) Metabolic and functional protection by selective inhibition of nitric oxide synthase 2 during ischemia-reperfusion in isolated perfused hearts. Circulation 109:1668-73
Szabolcs, Matthias J; Sun, Ji; Ma, Ningsheng et al. (2002) Effects of selective inhibitors of nitric oxide synthase-2 dimerization on acute cardiac allograft rejection. Circulation 106:2392-6
Szabolcs, M J; Ma, N; Athan, E et al. (2001) Acute cardiac allograft rejection in nitric oxide synthase-2(-/-) and nitric oxide synthase-2(+/+) mice: effects of cellular chimeras on myocardial inflammation and cardiomyocyte damage and apoptosis. Circulation 103:2514-20
Yang, X; Ma, N; Szabolcs, M J et al. (2000) Upregulation of COX-2 during cardiac allograft rejection. Circulation 101:430-8
Fard, A; Tuck, C H; Donis, J A et al. (2000) Acute elevations of plasma asymmetric dimethylarginine and impaired endothelial function in response to a high-fat meal in patients with type 2 diabetes. Arterioscler Thromb Vasc Biol 20:2039-44
Szabolcs, M J; Cannon, P J; Thienel, U et al. (2000) Analysis of CD154 and CD40 expression in native coronary atherosclerosis and transplant associated coronary artery disease. Virchows Arch 437:149-59
Ravalli, S; Albala, A; Ming, M et al. (1998) Inducible nitric oxide synthase expression in smooth muscle cells and macrophages of human transplant coronary artery disease. Circulation 97:2338-45
Cannon, P; Yang, X; Szabolcs, M J et al. (1998) The role of inducible nitric oxide synthase in cardiac allograft rejection. Cardiovasc Res 38:6-15
Szabolcs, M J; Ravalli, S; Minanov, O et al. (1998) Apoptosis and increased expression of inducible nitric oxide synthase in human allograft rejection. Transplantation 65:804-12

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