title: MT1-MMP-dependent remodeling of cardiac extracellular matrix structure and function following myocardial infarction.
abstract: The myocardial extracellular matrix (ECM), an interwoven meshwork of proteins, glycoproteins, proteoglycans, and glycosaminoglycans that is dominated by polymeric fibrils of type I collagen, serves as the mechanical scaffold on which myocytes are arrayed for coordinated and synergistic force transduction. Following ischemic injury, cardiac ECM remodeling is initiated via localized proteolysis, the bulk of which has been assigned to matrix metalloproteinase (MMP) family members. Nevertheless, the key effector(s) of myocardial type I collagenolysis both in vitro and in vivo have remained unidentified. In this study, using cardiac explants from mice deficient in each of the major type I collagenolytic MMPs, including MMP-13, MMP-8, MMP-2, MMP-9, or MT1-MMP, we identify the membrane-anchored MMP, MT1-MMP, as the dominant collagenase that is operative within myocardial tissues in vitro. Extending these observations to an in vivo setting, mice heterozygous for an MT1-MMP-null allele display a distinct survival advantage and retain myocardial function relative to wild-type littermates in an experimental model of myocardial infarction, effects associated with preservation of the myocardial type I collagen network as a consequence of the decreased collagenolytic potential of cardiac fibroblasts. This study identifies MT1-MMP as a key MMP responsible for effecting postinfarction cardiac ECM remodeling and cardiac dysfunction.
authors.affiliation: Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109-2216, USA.
authors.forename: Gerald C
authors.initials: GC
authors.lastname: Koenig
authors.forename: R Grant
authors.initials: RG
authors.lastname: Rowe
authors.forename: Sharlene M
authors.initials: SM
authors.lastname: Day
authors.forename: Farideh
authors.initials: F
authors.lastname: Sabeh
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Atkinson
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Cooke
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Weiss
mesh_terms: D000818:Animals; D024042:Collagen Type I / Q000378:metabolism; D005109:Extracellular Matrix / Q000201:enzymology* / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D017403:In Situ Hybridization; D053511:Matrix Metalloproteinase 14 / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000378:metabolism; D009924:Organ Culture Techniques; D014463:Ultrasonography; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D024042:Collagen Type I; D053511:Matrix Metalloproteinase 14