This application arises from observations made in the last six years while examining the cellular and molecular role of inflammation in the regulation of cardiac repair. The studies were directed at understanding the potential role of 1) chemokine regulation and 2) marrow-derived blood-borne precursors in cardiac injury and repair. As part of these studies, we defined a model of fibrotic cardiomyopathy in the mouse arising from daily, non-lethal coronary occlusion and reperfusion (I/RC). Both the fibrosis and the myocardial dysfunction are obviated by 1) overexpression of extracellular SOD and 2) deletion or antibody inhibition of MCP-1. Our data suggest that the non-adaptive fibrosis is associated with the uptake of marrow-derived blood-borne fibroblast precursors. Non-adaptive fibrosis and remodeling in coronary artery disease is clearly one of the leading causes of heart failure and death even in the absence of infarction. The primary model to be studied in this grant period involves this fibrotic cardiomyopathy (I/RC) in the mouse developing in the absence of myocardial infarction. This model offers the opportunity to concentrate on the role of dysregulation of chemokine expression and the uptake and maturation of the marrow-derived blood- borne fibroblast precursors which generate the activated fibroblasts associated with non-adaptive cardiac fibrosis. Specific Aim 1 - Characterize and quantitate factors mediating the uptake and maturation of blood-derived fibroblast precursors which mediate non-adaptive fibrosis in I/RC. Specific Aim 2 - Examine the cellular and molecular mechanisms of interventions which we have shown to obviate I/RC by specifically altering the growth of blood-derived precursors and/or their maturation into secretory fibroblasts in vivo and in vitro. We will examine the cellular and molecular consequences of: a) treatment with serum amyloid P and b) Rho kinase (ROCK1) deletion. We will also examine the effect of IP10, a CXC chemokine that inhibits fibrosis by modulating fibroblast function and impairs myocardial scar formation following infarction.
NIH ExPorter
NIH ExPorter