Abstract 4392: Cardiac Restricted Over-Expression of Extracellular Matrix Metalloproteinase Inducer (EMMPRIN) Causes Myocardial Remodeling and Dysfunction in Aging Mice
The matrix metalloproteinases (MMPs) play a pivotal role in adverse left ventricular (LV) myocardial remodeling. The transmembrane protein, extracellular matrix metalloproteinase 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 2-fold increase in EMMPRIN when compared to age/strain matched wild type mice (WT). EMMPRINexp and WT mice were examined at 3±1 (n=12,15) and at 14±1 months of age (n=12,7) LV end-diastolic volume (EDV) and ejection fraction were similar in young EMMPRINexp and WT mice (62±5 vs 58±2 uL, 52±1 vs 57±2 %, respectively). However, in old EMMPRINexp mice, LV EDV increased (95±7 vs 68±5 uL, p<0.05) when compared to old WT values and LV EF was reduced (48±3%, p<0.05). In EMMPRINexp old mice, myocardial MMP-2 and membrane type-1 MMP levels were increased by over 50% from WT values (p<0.05) and was accompanied by a 2-fold higher collagen content (p<0.05). Increased myocardial EMMPRIN expression caused increased levels of both soluble and membrane type MMPs, fibrosis, and was associated with adverse LV remodeling as a function of age. These findings suggest that EMMPRIN is an upstream signaling pathways which can play a mechanistic role in adverse remodeling within the myocardium.