Left ventricular (LV) myocardial remodeling invariably occurs post-myocardial infarction (MI) and can lead to LV dilation and pump dysfunction. A critical structural event in the post-MI remodeling process is alterations within the extracellular matrix (ECM). The matrix metalloproteinases (MMPs) constitute a family of proteolytic enzymes responsible for ECM degradation and a cause-effect relationship between MMP activation and LV myocardial remodeling has been established. The central hypothesis of this project is that a time and region specific induction of a unique MMP species occurs within the myocardium post-MI and contributes to the progression of heterogeneous LV remodeling. A recently discovered class of MMPs is the MT-MMPs, which are membrane bound and provide a focalized area for ECM degradation as well as activate other MMPs. MTMMPs are proteolytically active once inserted into the cell membrane and therefore critical control points for activity are transcriptional/translational events. Increased levels of the well-characterized MT-MMP, MT1-MMP have been observed in patients and animals with LV remodeling and failure, but are not upregulated in normal wound healing and tissue turnover. Accordingly, this project will: 1) Test the hypothesis that a localized induction and activation of MT1-MMP occurs in concert with the adverse LV myocardial remodeling post-MI. 2) Test the hypothesis that enhanced induction of MT1-MMP within the post-MI myocardium will accelerate MI expansion, LV dilation and subsequent pump failure. 3) Test the hypothesis that in post-MI remodeling, regional differences in MT1-MP expression and post-transcriptional processing occur within the myocardial cell type critical to ECM remodeling: the fibroblast. These studies will be performed using a well characterized porcine model of MI, novel fluorogenic microdialysis methods, targeted myocardial adenoviral transduction of MT1-MMP, MT1- MMP cardiac restricted over-expression in mice, and unique methods to measure MT1-MMP translational efficiency in myocardial fibroblasts. The outcomes from these studies will define how local MT1-MMP expression contributes to post-MI remodeling. These results will yield new insights into a local proteolytic system and allow for the development of targeted strategies to modify the remodeling that follows myocardial infarction.
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