Abstract 12438: Effects of Pressure-Overload Induced Left Ventricular Remodeling on Membrane Type-1 Matrix Metalloproteinase Promoter Activation and Expression
Background: Pressure-overload causes left ventricular (LV) remodeling with one of the structural milestones of this process being extracellular matrix remodeling and fibrosis. While the regulation of matrix metalloproteinases (MMPs) likely plays a role in this process, the induction and mechanistic role of specific MMPs is poorly understood. Recent in-vivo studies have suggested that the transmembrane MMP, MT1-MMP can actually induce a profibrotic process and thereby effect matrix remodeling and fibrosis in PO. This study tested the hypothesis that in-vivo induction of MT1-promoter activity and expression occurs with PO.
Methods: MT1-MMP promoter activity (MT1-PROM act) was measured by generating a transgenic mouse (FVB; full length human MT1-MMP promoter ligated to the firefly luciferase gene). MT1-MMP PROM reporter mice underwent PO (4 weeks transverse aortic constriction n = 13) and were compared to non-banded controls (n = 10). In-vivo MT1-PROM act was quantified by luciferase mRNA expression. LV echocardiography was used to measure LV end-diastolic volume (EDV), ejection fraction (EF) and LV mass / body weight (LV/BW). Total endogenous MT1-MMP mRNA (fold change from control) was determined by rtPCR and collagen volume fraction was determined histologically using picrosirius red.
Results: TAC resulted in pressure-overload hypertrophy, increased matrix fibrosis, increased MT1-MMP promoter activation, and increased MT1-MMP mRNA expression (Table).
Conclusions: The unique findings of this study are that MT1-MMP promoter activity, measured in an intact system, was increased in PO and resulted in a 5-fold increase in MT1-MMP mRNA. These findings suggest that increased MT1-MMP may play a pivotal role in pressure-overload induced LV remodeling and fibrosis.
- © 2010 by American Heart Association, Inc.