Key result
In mice subjected to pressure overload, MT1-MMP overexpression increased collagen content by 60% and left atrial dimension by 19% compared to wild-type, demonstrating its role in maladaptive remodeling.
Why the study?
Does altering MT1-MMP expression affect the myocardial matrix remodeling response to pressure overload in mice?
Does altering MT1-MMP expression affect the myocardial matrix remodeling response to pressure overload in mice?
Altering MT1-MMP levels directly modulates the maladaptive matrix remodeling and myocardial fibrotic response to pressure overload in mice.
MT1-MMP modulation may mitigate pressure-overload remodeling; hypothesis-generating in mice, human translation untested.
BACKGROUND: Although matrix metalloproteinases (MMPs) were initially thought to result primarily in extracellular matrix degradation, certain MMP types, such as membrane type-1 (MT1) MMP, may also be involved in profibrotic cascades through hydrolysis of latency-associated transforming growth factor-binding protein (LTBP-1) and activation of transforming growth factor-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 overexpression or MT1-MMP reduced expression 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. Although LV mass was similar among WT, MT1-MMP overexpression, and MT1-MMP reduced expression after PO, significant differences in LV function, MT1-MMP-mediated LTBP-1 hydrolysis, and collagen content occurred. PO in MT1-MMP overexpression increased LTBP-1 hydrolysis (18%), collagen content (60%), and left atrial dimension (19%; indicative of LV diastolic dysfunction) when compared with WT. PO in MT1-MMP reduced expression reduced left atrial dimension (19%), LTBP-1 hydrolysis (40%), and collagen content (32%) when compared with 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 PO.
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Zile et al. (2014) studied Left ventricular pressure overload. MT1-MMP overexpression or reduced expression vs. Wild-type mice was evaluated on Matrix remodeling response (LV mass, LTBP-1 hydrolysis, collagen content, left atrial dimension). In mice subjected to pressure overload, MT1-MMP overexpression increased collagen content by 60% and left atrial dimension by 19% compared to wild-type, demonstrating its role in maladaptive remodeling.
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