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.


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 approximately 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 approximately 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.
Spinale
Francis G
FG
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, SC 29425, USA.
Escobar
G Patricia
GP
Mukherjee
Rupak
R
Zavadzkas
Juozas A
JA
Saunders
Stuart M
SM
Jeffords
Laura B
LB
Leone
Allyson M
AM
Beck
Christy
C
Bouges
Shenikqua
S
Stroud
Robert E
RE
D000375:Aging / Q000235:genetics*; D000818:Animals; D015870:Gene Expression; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis*; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000235:genetics*
D053511:Matrix Metalloproteinase 14