Cardiac-restricted overexpression of extracellular matrix metalloproteinase inducer causes myocardial remodeling and dysfunction in aging mice

Medical University of South Carolina and the Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina Submitted 2 April 2008 ; accepted in final form 4 August 2008 The matrix metalloproteinases (MMPs) play a pivotal role in adverse left ventricular (LV) myocardial remodeling. The transmembrane protein extracellular MMP inducer (EMMPRIN) causes increased MMP expression in vitro, and elevated levels occur in patients with LV failure. However, the direct consequences of a prolonged increase in the myocardial expression of EMMPRIN in vivo remained unexplored. Cardiac-restricted EMMPRIN expression (EMMPRINexp) was constructed in mice using the full-length human EMMPRIN gene ligated to the myosin heavy chain promoter, which yielded approximately a twofold increase in EMMPRIN compared with that of the age/strain-matched wild-type (WT) mice; EMMPRINexp ( n = 27) and WT ( n = 33) mice were examined at 3.2 ± 0.1 or at 13.3 ± 0.5 mo of age ( n = 43 and 26, respectively). LV end-diastolic volume (EDV) was similar in young EMMPRINexp and WT mice (54 ± 2 vs. 57 ± 3 µl), but LV ejection fraction (EF) was reduced (51 ± 1 vs. 57 ± 1%; P < 0.05). In old EMMPRINexp mice, LV EDV was increased compared with WT mice values (76 ± 3 vs. 58 ± 3 µl; P < 0.05) and LV EF was significantly reduced (45 ± 1 vs. 57 ± 2%; P < 0.05). In EMMPRINexp old mice, myocardial MMP-2 and membrane type-1 MMP levels were increased by >50% from WT values ( P < 0.05) and were accompanied by a twofold higher collagen content ( P < 0.05). Persistent myocardial EMMPRINexp in aging mice caused increased levels of both soluble and membrane type MMPs, fibrosis, and was associated with adverse LV remodeling. These findings suggest that EMMPRIN is an upstream signaling pathway that can play a mechanistic role in adverse remodeling within the myocardium. ventricular function Address for reprint requests and other correspondence: F. G. Spinale, Cardiothoracic Surgery, Rm. 625, 770 MUSC Complex, 114 Doughty St., Charleston, SC 29425 (e-mail: wilburnm{at}musc.edu )