Chronic rejection in the transplanted heart is associated with interstitial fibrosis and progressive neointimal lesion formation in the coronary arterial bed that impairs tissue perfusion to the point of functional disruption. Our intention in Project 3 is to examine wound repair processes in the transplanted heart that specifically involve activated stromal myofibroblasts. We propose that alloantigen-independent ischemia/reperfusion injury during the early post-operative period as well as chronic, alloantigen-dependent release of TGFbeta1 in long-term accepted grafts promote myofibroblasts activation and histogenic remodeling via a common signaling pathways based on reactive oxygen species (ROS). Myofibroblasts accumulate in the coronary adventitia and cardiac interstitium of heart grafts where they express several injury- response genes that are regulated by MSYI, a cold-shock domain (CSD) transcriptional regulatory protein. MSY1 and related proteins are important mediators of the transcriptional response to tissue stress and redox imbalance. The goal of the proposed research is to examine TGFbeta1- and ROS-dependent changes in MSY1 protein complexes that govern VSM alpha-actin promoter activity. Mis-regulation of VSM alpha-actin expression during chronic rejection is associated with accumulation of myofibroblasts, fibrocontractile scar tissue, neointimal smooth muscle cells, and poorly differentiated cardiomyocytes. VSM alpha-actin is encoded by a prototypical injury response gene that shares MSY1 control elements with other genes required for wound repair. Analysis of interactions between MSY1 and other TRPs required for injury-response gene expression in human stromal myofibroblasts should provide new information about molecular control points in chronic rejection. In human pathology and intramyocardial biopsy samples, assessment of MSY1:TRP structure and function may provide new prognostic indicators for evaluating and staging chronic rejection in transplant patients before the development of graft-destructive fibrosis. From the standpoint of transplant vascular sclerosis, studiers of stromal myofibroblasts are especially relevant given the demonstrated importance of adventitial fibroblasts in neointima formation as well as the establishment of new microvascular perfusion circuits that are critical for long-term heart graft survival. Finally, TGFbeta1 and/or ROS may modulate expression of other MSY1-dependent, chronic rejection- associated genes such as those encoding MHC class II molecules which compliments Project 1 and 2 aims pertaining to alloantibody production, monocyte/macrophage FcR engagement, and the role of TGFbeta1 in graft acceptance vs. fibrosis.
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