Abstract 12796: Direct Regulation of Myocardial Membrane Type-1 Following Myocardial Infarction Causes Changes in Survival, Function and Remodeling
Background: Membrane type-1 matrix metalloproteinase (MT1-MMP) is a unique member of the large family of MMPs, displays a large proteolytic portfolio, and is increased in humans and animals with left ventricular (LV) remodeling and failure. However, the direct effects of modulating MT1-MMP in the context of the natural history of LV remodeling, such as post-myocardial infarction (MI), remains to be defined.
Methods/Results: Following baseline echo measurements of LV ejection fraction (LVEF) and end-diastolic volume (LVEDV), MI was induced in mice with cardiac restricted over-expression of MT1-MMP (MT1-MMPexp; full length human; n=77), reduced MT1-MMP expression (heterozygous; MT1-MMP+/−; n=20), and wild type (WT; n=90) and measurements repeated at 2 weeks. Post-MI survival was significantly lower in MT1-MMPexp compared to WT-MI (42 vs 59%, p<0.05) and was significantly improved in the MT1-MMP+/− group (90%, p<0.05). LVEF was lower in the MT1-MMPexp compared to WT, whereas LVEF was higher and LVEDV lower in the MT1-MMP+/− group (Table). When compared to non-MI WT (n=10), MT1-MMP activity by a validated fluorogenic substrate was higher following MI, increased further with MT1-MMPexp and was reduced with MT1-MMP+/−, whereas collagen content (COLL) by histochemistry was increased in MT1-MMPexp and reduced with MT1-MMP+/− (Table).
Conclusions: These new findings demonstrate that regulation of myocardial MT1-MMP levels directly cause changes in post-MI survival and LV remodeling. Thus, MT1-MMP is a likely proteolytic lynchpin in the progression to LV remodeling and failure.
- © 2010 by American Heart Association, Inc.