期刊
CIRCULATION-HEART FAILURE
卷 2, 期 4, 页码 351-360出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCHEARTFAILURE.108.844845
关键词
matrix; myocardial remodeling; ventricular function; aging
资金
- National Institutes of Health [HL059165, PO I HL048788, HL078650]
- Veterans' Affairs Health Administration
Background-The direct consequences of a persistently increased myocardial expression of the unique matrix metallo-proteinase (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 approximate to 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 approximate to 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. (Circ Heart Fail. 2009;2:351-360.)
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