Abstract 13207: Role of Membrane Type-1 Matrix Metalloproteinase Expression in Pressure-Overload Induced Left Ventricular Remodeling
Background: Pressure-overload (PO) causes left ventricular (LV) remodeling characterized by myocyte hypertrophy, and interstitial fibrosis. One mechanism thought to effect this remodeling process is an alteration in matrix metalloproteinase (MMP) activity. Recent in-vivo studies have suggested that the transmembrane MMP, MT1-MMP, can induce a profibrotic process, and thereby effect LV remodeling and fibrosis. The purpose of this study was to test the hypothesis that a change in MT1-MMP expression will alter the structural and functional response to PO.
Methods: MT1-MMP expression was altered by creating 2 transgenic mice: MT1-MMP over-expresser (MT1-OE, using alpha myosin heavy chain promoter linked to full length human MT1-MMP); MT1-MMP reduced-expresser (MT1-RE, using a heterozygous mouse with a critical fragment of the MT1-MMP gene [exon 4] replaced with a neomycin cassette, 50% reduction in MT1-MMP gene copy and MT1-MMP protein levels). The effects of PO (4 weeks transverse aortic constriction, TAC) were examined in FVB wild type control (WT n= 33), MT1-OE (n= 64) and MT1-RE (n=24) using echocardiography to measure LV end-diastolic volume (EDV), ejection fraction (EF) and LV mass / body weight (LV/BW). MT1-MMP activity was assessed using a quenched fluorogenic peptide substrate assay. Collagen volume fraction was determined histologically using picrosirius red.
Results: Following TAC compared with WT, MT1-OE mice had increased MT1-MMP expression and activity that resulted in increased fibrosis, remodeling, and mortality; by contrast, MT1-RE mice had decreased MT1-MMP expression and activity that resulted in decreased fibrosis, remodeling, and mortality (Table).
Conclusions: These novel studies demonstrate that MT1-MMP plays a pivotal role in the myocardial response to pressure-overload. MT1-MMP induces a profibrotic response which leads to maladaptive remodeling, fibrosis and decreased survival.
- © 2010 by American Heart Association, Inc.