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.
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