Cardiac-Restricted Overexpression of Membrane Type-1 Matrix Metalloproteinase in Mice Effects on Myocardial Remodeling With Aging

Background —The direct consequences of a persistently increased myocardial expression of the unique matrix metalloproteinase (MMP), membrane type-1 (MT1-MMP) on myocardial remodeling remained unexplored. Methods and Results —Cardiac restricted MT1-MMPexp was constructed in mice using the full length human MT1-MMP gene ligated to the myosin heavy chain promoter, which yielded approximately a 200% increase in MT1-MMP when compared to age/strain matched wild type mice (WT). LV function and geometry was assessed by echocardiography in 3 month ("young") WT (n=32) and MT1-MMPexp (n=20) mice, and compared to 14 month ("middle age") WT (n=58) and MT1-MMPexp (n=35) mice. LV end-diastolic volume was similar between the WT and MT1-MMPexp young groups as was LV ejection fraction. In the middle age WT mice, LV end-diastolic volume and ejection fraction was similar to young WT mice. However, in the MT1-MMPexp middle age mice, LV end-diastolic volume was approximately 43% higher and LV ejection fraction 40% lower (both p<0.05). Moreover, in the middle age MT1-MMPexp mice, myocardial fibrillar collagen increased by nearly 2-fold and was associated with an approximate 3-fold increase in the processing of the pro-fibrotic molecule, latency-associated transforming growth factor binding protein. In a second study, 14 day survival following myocardial infarction was significantly lower in middle aged MT1-MMPexp mice. Conclusions —Persistently increased myocardial MT1-MMP expression, in and of itself, caused LV remodeling, myocardial fibrosis, dysfunction and reduced survival following myocardial injury. These findings suggest that MT1-MMP plays a mechanistic role in adverse remodeling within the myocardium.