Abstract 3875: Cardiac Restricted Over-Expression of Membrane Type-1 Matrix Metalloproteinase in Mice: Effects on Myocardial Remodeling with Aging
While the induction of matrix metalloproteinases (MMPs) contributes to adverse myocardial remodeling, specific MMP types that directly cause this process remain unknown. One unique MMP type is the membrane type-1 MMP (MT1-MMP) that possesses a diverse proteolytic portfolio including activation of other MMPs such as MMP-2, and increased levels (~2 fold) occur in patients with severe LV failure. This study tested the hypothesis that selective induction of myocardial MT1-MMP expression (MT1-MMPexp) would cause LV remodeling and dysfunction, particularly with age. 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 echo in 3 month (“young”) WT (n=13) and MT1-MMPexp (n=12) mice, and compared to 14 month (“old”) WT (n=18) and MT1-MMPexp (n=12) mice. LV end-diastolic volume was similar between the WT and MT1-MMPexp young groups (43±2, 47±3 uL, respectively) as was LV ejection fraction (65±2, 61±2%, respectively). In the old WT mice, LV end-diastolic volume and ejection fraction was similar to young WT mice (47±3 uL, 61±2%, respectively). In marked contrast however, LV end-diastolic volume was approximately 2-fold higher in the old MT1-MMPexp mice when compared to old WT values (87±10 uL, p<0.05), and LV ejection fraction was significantly reduced (46±3%, p<0.05). Moreover, in the old MT1-MMPexp mice, myocardial fibrillar collagen was increased by nearly 2-fold compared to age matched WT (hydroxyproline; 4.3±0.4 vs 2.2±0.2, ng/mg, p<0.05). Finally, myocardial levels of MMP-2, particularly of the active form, were increased by over 2-fold in the old MT1-MMPexp mice compared to WT (p<0.05). These unique findings demonstrated that persistently increased myocardial MT1-MMPexp, to levels previously observed in patients with LV failure, resulted in LV dilation and systolic dysfunction. Moreover, MT1-MMPexp was accompanied by heightened MMP-2 activation and fibrosis as a function of age. Thus, increased MT1-MMP plays a mechanistic role in adverse myocardial remodeling.