Abstract 12801: Altering Myocardial Membrane Type-1 Following Myocardial Infarction Directly Affects LV Remodeling and Function Through a Novel Fibrotic Signaling Cascade
Background: While the membrane type-1 matrix metalloproteinase (MT1-MMP) is increased in humans and animals with left ventricular (LV) failure, the direct effects of regulating myocardial MT1-MMP levels on LV remodeling such as following myocardial infarction (MI), and the proteolytic substrates involved in this process have not been explored.
Methods/Results: MI was induced in mice with cardiac restricted over-expression of MT1-MMP (MT1-MMPexp; full length human; n=32), reduced MT1-MMP expression (heterozygous; MT1-MMP+/−; n=18). LV ejection fraction was lower in the post-MI MT1-MMPexp mice compared to WT (37±2 vs 29±1%, p<0.05), and was higher in the MT1-MMP +/− mice (44±1%, both p<0.05). LV collagen content was higher in the MT1-MMPexp vs WT post-MI, and reduced in the MT1-MMP+/− group (90±1, 85±1, vs 77±2%, p<0.05 respectively). Using a validated fluorogenic construct, it was discovered that MT1-MMP proteolytically processed the pro-fibrotic molecule, latency-associated transforming growth factor (TGF)-1 binding protein (LTBP-1), and MT1-MMP specific LTBP-1 proteolytic activity was increased by over 4-fold in the post-MI MT1-MMPexp group and reduced in the MT1-MMP+/− and this specific MT1-MMP mediated LTBP-1 proteolysis was directly paralleled in phospho-Smad-3 levels; a critical TGF signaling component (Figure).
Conclusions: Modulating myocardial MT1-MMP levels directly affected LV function and matrix structure, and a contributory molecular mechanism for these effects is through processing of profibrotic signaling molecules. Thus, a proteolytically diverse portfolio exists for MT1-MMP within the myocardium and plays a mechanistic role in adverse LV remodeling.
- © 2010 by American Heart Association, Inc.