title: Cardiac-restricted overexpression of extracellular matrix metalloproteinase inducer causes myocardial remodeling and dysfunction in aging mice.
abstract: 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 microl), 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 microl; 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.
authors.affiliation: Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Juozas A
authors.initials: JA
authors.lastname: Zavadzkas
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Plyler
authors.forename: Shenikqua
authors.initials: S
authors.lastname: Bouges
authors.forename: Christine N
authors.initials: CN
authors.lastname: Koval
authors.forename: William T
authors.initials: WT
authors.lastname: Rivers
authors.forename: Christy U
authors.initials: CU
authors.lastname: Beck
authors.forename: Eileen I
authors.initials: EI
authors.lastname: Chang
authors.forename: Robert E
authors.initials: RE
authors.lastname: Stroud
authors.forename: Rupak
authors.initials: R
authors.lastname: Mukherjee
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
mesh_terms: D000367:Age Factors; D000375:Aging; D000818:Animals; D051926:Basigin / Q000235:genetics / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D004452:Echocardiography; D005355:Fibrosis; D006801:Humans; D007150:Immunohistochemistry; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013318:Stroke Volume; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D020257:Ventricular Remodeling
chemical_list: C497886:BSG protein, human; C507096:Mmp14 protein, mouse; D051926:Basigin; D003094:Collagen; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D053511:Matrix Metalloproteinase 14