title: 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.
authors.affiliation: Medical University of South Carolina and Ralph H. Johnson Veteran's Affairs Medical Center, Charleston, South Carolina 29425, USA.
authors.forename: Juozas A
authors.initials: JA
authors.lastname: Zavadzkas
authors.forename: Rupak
authors.initials: R
authors.lastname: Mukherjee
authors.forename: William T
authors.initials: WT
authors.lastname: Rivers
authors.forename: Risha K
authors.initials: RK
authors.lastname: Patel
authors.forename: Evan C
authors.initials: EC
authors.lastname: Meyer
authors.forename: Laurel E
authors.initials: LE
authors.lastname: Black
authors.forename: Richard A
authors.initials: RA
authors.lastname: McKinney
authors.forename: J Marshall
authors.initials: JM
authors.lastname: Oelsen
authors.forename: Robert E
authors.initials: RE
authors.lastname: Stroud
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D053779:Latent TGF-beta Binding Proteins / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000201:enzymology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051899:Smad2 Protein / Q000096:biosynthesis / Q000235:genetics; D013534:Survival; D016277:Ventricular Function, Left / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D053779:Latent TGF-beta Binding Proteins; C509033:Ltbp1 protein, mouse; C507096:Mmp14 protein, mouse; D012333:RNA, Messenger; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D003094:Collagen; D053511:Matrix Metalloproteinase 14