Cardiac-restricted overexpression of extracellular matrix metalloproteinase inducer causes myocardial remodeling and dysfunction in aging mice
| Autor: | Christy Beck, Robert E. Stroud, Christine N. Koval, Rebecca A Plyler, Juozas A. Zavadzkas, Francis G. Spinale, Eileen I. Chang, William T Rivers, Shenikqua Bouges, Rupak Mukherjee |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Pathology
medicine.medical_specialty Aging Physiology Mice Transgenic Biology Matrix metalloproteinase Extracellular matrix Mice Ventricular Dysfunction Left Fibrosis Physiology (medical) medicine Extracellular Matrix Metalloproteinase 14 Animals Humans Inducer Ventricular remodeling Metalloproteinase Ventricular Remodeling Myocardium Age Factors Editorial Focus Stroke Volume Articles medicine.disease Immunohistochemistry Up-Regulation Echocardiography Cancer research Basigin Matrix Metalloproteinase 2 Collagen Signal transduction Cardiology and Cardiovascular Medicine Signal Transduction |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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