The Role of Macrophage-derived MMPs in LV Remodeling

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DESCRIPTION (provided by applicant): Despite current therapeutic strategies to restore blood flow to the ischemic myocardium and limit infarct size, adverse left ventricular (LV) remodeling that progresses to congestive heart failure (CHF) remains a significant complication following myocardial infarction (MI). The extracellular matrix (ECM) is a key component in the remodeling process following an MI, and increases in collagen occur in the infarct area to replace necrotic myocytes and form a scar. The macrophage is a chronic inflammatory cell that mediates LV remodeling during the healing phase post-Ml. Macrophages are key producers of and reactors to matrix metalloproteinases (MMPs), a family of enzymes that regulate matrix turnover during this remodeling process. Several laboratories have demonstrated MMP participation in remodeling events, and inhibition or the targeted deletion of specific MMPs (particularly MMP-9) have beneficial effects following MI. Thus, an understanding of how macrophages and macrophage-derived MMPs -7 and -9 regulate the matrix-mediated healing process in response to an MI will provide insight into the mechanisms of LV remodeling. In addition, the growing concept of non-matrix regulated MMP proteolysis illustrates that primary MMP functions may be matrix-independent. In Specific Aim 1, we will study the role(s) of macrophages in early LV remodeling using mice with a targeted deletion of monocyte chemotactic protein-1 (MCP-1). This aim will expand on preliminary work demonstrating a critical role for the macrophage in infarct remodeling. Specific Aim 2 will examine the functional role of macrophage-specific overexpression of MMP-7 and MMP-9 on macrophage functions and remodeling events. Finally, in Specific Aim 3, we will use the emerging technology of proteomics to identify novel non-matrix MMP substrates in the macrophage that may play a role in LV remodeling.