We propose to investigate the role that early myocardial oxadative stress signaling pathways have in the development of graft coronary artery disease (GCAD) following cardiac transplantation. In the established PVG donor to ACI recipient rat model, expression of bcl-2 decreases and nuclear factor kappa-B (NFkB) activity increases in the early reperfusion period. Inhibition of NFkB reduces reperfusion injury and GCAD in this model. In other models of ischemia and reperfusion BCL-2 has been shown to regulate NFkB activity. The overall hypothesis of this proposal is that myocardial oxidative stress following cardiac transplantation contributes to the development of graft coronary artery disease via a bcl-2 associated mechanism.
The specific aims of the proposed work are: 1) To delineate the dependence of early myocardial oxidative stress and NFkB activity on bcl-2 expression following cardiac transplantation; 2) To determine the effects of decreased or increased myocardial oxidative stress on bcl-2 expression and NFkB activity following cardiac transplantation; and 3) To determine the role that early post-transplantation myocardial bcl-2 expression and intracellular localization plays in the later development of graft coronary artery disease. This proposal utilizes transgenic mice to more clearly characterize the role that bcl-2 plays in NFkB activation and in the development of myocardial oxidative stress following cardiac transplantation. The knowledge gained in the transgenic experiments will contribute to the overall understanding of the effects of bcl-2 overexpression on the development of GCAD in the PVG to ACI model. Upon completion of this study, we will have demonstrated the potential of altering the signaling pathways of oxidative stress by graft specific modulation, which may have applicability for other solid organ transplantation and as a myocardial protection strategy for routine cardiac surgical procedures.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL065669-02
Application #
6537882
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Massicot-Fisher, Judith
Project Start
2001-04-01
Project End
2005-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
2
Fiscal Year
2002
Total Cost
$314,150
Indirect Cost
Name
Stanford University
Department
Surgery
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Tanaka, Masashi; Gunawan, Feny; Terry, Raya D et al. (2005) Inhibition of heart transplant injury and graft coronary artery disease after prolonged organ ischemia by selective protein kinase C regulators. J Thorac Cardiovasc Surg 129:1160-7
Tanaka, Masashi; Fedoseyeva, Eugenia V; Robbins, Robert C (2005) Graft coronary artery disease in murine cardiac allografts: proposal to meet the need for standardized assessment. J Heart Lung Transplant 24:316-22
Tanaka, Masashi; Mokhtari, Golnaz K; Balsam, Leora B et al. (2005) Cyclosporine mitigates graft coronary artery disease in murine cardiac allografts: description and validation of a novel fully allogeneic model. J Heart Lung Transplant 24:446-53
Tanaka, Masashi; Sydow, Karsten; Gunawan, Feny et al. (2005) Dimethylarginine dimethylaminohydrolase overexpression suppresses graft coronary artery disease. Circulation 112:1549-56
Tanaka, Masashi; Mokhtari, Golnaz K; Terry, Raya D et al. (2005) Prolonged cold ischemia in rat cardiac allografts promotes ischemia-reperfusion injury and the development of graft coronary artery disease in a linear fashion. J Heart Lung Transplant 24:1906-14
Balsam, Leora B; Mokhtari, G Kimia; Jones, Sophie et al. (2005) Early inhibition of caspase-3 activity lessens the development of graft coronary artery disease. J Heart Lung Transplant 24:827-32
Tanaka, Masashi; Swijnenburg, Rutger-Jan; Gunawan, Feny et al. (2005) In vivo visualization of cardiac allograft rejection and trafficking passenger leukocytes using bioluminescence imaging. Circulation 112:I105-10
Tanaka, Masashi; Zwierzchoniewska, Monika; Mokhtari, Golnaz K et al. (2005) Progression of alloresponse and tissue-specific immunity during graft coronary artery disease. Am J Transplant 5:1286-96
Tanaka, Masashi; Nakae, Susumu; Terry, Raya D et al. (2004) Cardiomyocyte-specific Bcl-2 overexpression attenuates ischemia-reperfusion injury, immune response during acute rejection, and graft coronary artery disease. Blood 104:3789-96
Tanaka, Masashi; Terry, Raya D; Mokhtari, Golnaz K et al. (2004) Suppression of graft coronary artery disease by a brief treatment with a selective epsilonPKC activator and a deltaPKC inhibitor in murine cardiac allografts. Circulation 110:II194-9

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