Mechanistic Relationship Between MT1-MMP and the Myocardial Response to Pressure-Overload
Background—While matrix metalloproteinases (MMPs) were initially thought to primarily result in extracellular matrix degradation, certain MMP types such as membrane type-1 MMP (MT1-MMP) may also be involved in profibrotic cascades through hydrolysis of latency-associated transforming growth factor (TGF) binding protein (LTBP-1) and activation of TGF dependent profibrotic signaling. The present study tested the hypothesis that MT1-MMP plays a direct role in the matrix remodeling response to a left ventricular (LV) pressure overload (PO) stimulus.
Methods and Results—Wild-type (WT) and transgenic mice with cardiac restricted MT1-MMP over-expression (MT1-OE) or MT1-MMP reduced expression (MT1-RE) underwent PO for 4 weeks. PO resulted in a 57% increase in LV mass (no change in LV end diastolic volume, resulting in an increase in the LV mass / volume ratio consistent with concentric remodeling), a 60% increase in MT1-MMP mediated LTBP-1 hydrolysis, and a 190% increase in collagen content in WT mice. While LV mass was similar between WT, MT1-OE and MT1-RE following PO, significant differences in LV function, MT1-MMP mediated LTBP-1 hydrolysis and collagen content occurred. PO in MT1-OE increased LTBP-1 hydrolysis (18%) collagen content (60%), left atrial dimension (19%; indicative of LV diastolic dysfunction) compared with WT. PO in MT1-RE reduced LAD (19%), LTBP-1 hydrolysis (40%) and collagen content (32%) compared to both WT.
Conclusions—Despite an equivalent PO stimulus and magnitude of LV myocardial growth, altering MT1-MMP levels caused specific matrix dependent changes in remodeling, thereby demonstrating a mechanistic role in the development of the maladaptive remodeling and myocardial fibrotic response to pressure-overload.
- Received November 14, 2013.
- Accepted January 2, 2014.