Direct regulation of membrane type 1 matrix metalloproteinase following myocardial infarction causes changes in survival, cardiac function, and remodeling

Abstract

The membrane type 1 matrix metalloproteinase (MT1-MMP) is increased in left ventricular (LV) failure. However, the direct effects of altered MT1-MMP levels on survival, LV function, and geometry following myocardial infarction (MI) and the proteolytic substrates involved in this process remain unclear. MI was induced in mice with cardiac-restricted overexpression of MT1-MMP (MT1-MMPexp; full length human), reduced MT1-MMP expression (heterozygous; MT1-MMP(+/-)), and wild type. Post-MI survival was reduced with MT1-MMPexp and increased with MT1-MMP(+/-) compared with WT. LV ejection fraction was lower in the post-MI MT1-MMPexp mice compared with WT post-MI and was higher in the MT1-MMP(+/-) mice. In vivo localization of MT1-MMP using antibody-conjugated microbubbles revealed higher MT1-MMP levels post-MI, which were the highest in the MT1-MMPexp group and the lowest in the MT1-MMP(+/-) group. LV collagen content within the MI region was higher in the MT1-MMPexp vs. WT post-MI and reduced in the MT1-MMP(+/-) group. Furthermore, it was demonstrated that MT1-MMP proteolytically processed the profibrotic molecule, latency-associated transforming growth factor-1-binding protein (LTBP-1), and MT1-MMP-specific LTBP-1 proteolytic activity was increased by over fourfold in the post-MI MT1-MMPexp group and reduced in the MT1-MMP(+/-) group, which was directionally paralleled by phospho-Smad-3 levels, a critical signaling component of the profibrotic transforming growth factor pathway. We conclude that modulating myocardial MT1-MMP levels affected LV function and matrix structure, and a contributory mechanism for these effects is through processing of profibrotic signaling molecules. These findings underscore the diversity of biological effects of certain MMP types on the LV remodeling process.

Mechanistic Relationship Between Membrane Type-1 Matrix Metalloproteinase and the Myocardial Response to Pressure Overload

“…Mice with a global reduction in expression of MT1-MMP (MT1-RE) were developed on an FVB background by replacing exon-4 of the murine MT1-MMP gene sequence with a neomycin cassette by homologous recombination, as previously described (18, 19). The global homozygous MT1-MMP knockout (−/−) animals display severe malformation and growth retardation, and typically die around postnatal day 21.…”

Matrix metalloproteinase collagenolysis in health and disease

“…In contrast, increased collagen catabolism over synthesis can lead to ventricular dilatation and systolic dysfunction [219]. MT1-MMP myocardial levels are increased post-myocardial infarction (MI) and coincident with adverse left ventricular remodeling [220, 221]. MT1-MMP is the dominant collagenase within myocardial tissues [221].…”

“…MT1-MMP is the dominant collagenase within myocardial tissues [221]. Following MI, MT1-MMP +/− mice have a survival advantage over MT1-MMP +/+ mice, while post-MI survival is reduced when MT1-MMP is overexpressed [220]. Survival has been correlated to decreased collagenolytic potential of cardiac fibroblasts (preservation of myocardial type I collagen network) [221].…”

Transient Collagen Triple Helix Binding to a Key Metalloproteinase in Invasion and Development

“…Tumor cells enmeshed in 3D collagen are restricted to spheroid morphology without growing or dividing, whereas MT1-MMP expression frees the tumor cells to grow and proliferate (Hotary et al, 2003). After myocardial infarction, increased cardiac expression of MT1-MMP decreases both left ventricular function and survival of mice (Zavadzkas et al, 2011). MT1-MMP is also over-expressed in atherosclerotic plaques, possibly destabilizing the plaques (Johnson et al, 2008) by degrading collagen (Schneider et al, 2008).…”