Published online before print May 8, 2009, doi: 10.1161/CIRCHEARTFAILURE.108.844845
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Original Articles |
Cardiac-Restricted Overexpression of Membrane Type-1 Matrix Metalloproteinase in Mice
Effects on Myocardial Remodeling With Aging
From the Divisions of Cardiothoracic Surgery, Medical University of South Carolina (F.G.S., G.P.E., R.M., J.A.Z., S.M.S., L.B.J., A.M.L., C.B., S.B., R.E.S.); and the Ralph H. Johnson Veteran’s Affairs Medical Center (F.G.S.), Charleston, SC.
Correspondence to Francis G. Spinale, MD, PhD, Cardiothoracic Surgery, Room 625, Medical University of South Carolina, 114 Doughty St, Charleston, SC 29425. E-mail wilburnm{at}musc.edu
Received April 16, 2008; accepted April 1, 2009.
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 with age/strain-matched wild-type (WT) mice. Left ventricular (LV) function and geometry was assessed by echocardiography in 3-month ("young") WT (n=32) and MT1-MMPexp (n=20) mice and compared with 14-month ("middle-aged") 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-aged WT mice, LV end-diastolic volume and ejection fraction was similar to young WT mice. However, in the MT1-MMPexp middle-aged mice, LV end-diastolic volume was 
43% higher and LV ejection fraction 40% lower (both P<0.05). Moreover, in the middle-aged MT1-MMPexp mice, myocardial fibrillar collagen increased by nearly 2-fold and was associated with 3-fold increase in the processing of the profibrotic molecule, latency-associated transforming growth factor binding protein. In a second study, 14-day survival after 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 after myocardial injury. These findings suggest that MT1-MMP plays a mechanistic role in adverse remodeling within the myocardium.
Key Words: matrix • myocardial remodeling • ventricular function • aging