title: Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction.
abstract: BACKGROUND
  Matrix metalloproteinases (MMPs) contribute to left ventricular remodeling after myocardial infarction (MI). Specific causative roles of particular MMPs, however, remain unclear. MMP-7 is abundant in cardiomyocytes and macrophages, but MMP-7 function after MI has not been defined.
  
  
  RESULTS
  Wild-type (WT; n=55) and MMP-7-null (MMP-7-/-; n=32) mice underwent permanent coronary artery ligation for 7 days. MI sizes were similar, but survival was greatly improved in MMP-7-/- mice. The survival difference could not be attributed to differences in left ventricular dilation because end-diastolic volumes increased similarly. ECG analysis revealed a prolonged PR interval in WT but not in MMP-7-/- post-MI mice. Post-MI conduction velocity, determined by optically mapping electrical wavefront propagation, decreased to 78+/-6% of control for WT and was normalized in MMP-7-/- mice. In WT mice, slower conduction velocity correlated with a 53% reduction in the gap junction protein connexin-43. Direct binding of MMP-7 to connexin-43, determined by surface plasmon resonance technology, occurred in a dose-dependent manner. Connexin-43 processing by MMP-7 was confirmed by in silico and in vitro substrate analyses and MMP-7 infusion induced arrhythmias in vivo.
  
  
  CONCLUSIONS
  MMP-7 deletion results in improved survival and myocardial conduction patterns after MI. This is the first report to implicate MMP-7 in post-MI remodeling and to demonstrate that connexin-43 is a novel MMP-7 substrate.
authors.affiliation: Cardiology Division, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr, Mail Code 7872, San Antonio, TX 78229-3900, USA. lindseym@uthscsa.edu
authors.forename: Merry L
authors.initials: ML
authors.lastname: Lindsey
authors.forename: G Patricia
authors.initials: GP
authors.lastname: Escobar
authors.forename: Rupak
authors.initials: R
authors.lastname: Mukherjee
authors.forename: Danielle K
authors.initials: DK
authors.lastname: Goshorn
authors.forename: Nina J
authors.initials: NJ
authors.lastname: Sheats
authors.forename: James A
authors.initials: JA
authors.lastname: Bruce
authors.forename: I Matthew
authors.initials: IM
authors.lastname: Mains
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Hendrick
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Hewett
authors.forename: Robert G
authors.initials: RG
authors.lastname: Gourdie
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Matrisian
authors.forename: Francis G
authors.initials: FG
authors.lastname: Spinale
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002450:Cell Communication; D018031:Connexin 43 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D004562:Electrocardiography; D017629:Gap Junctions / Q000737:chemistry / Q000473:pathology; D017353:Gene Deletion; D006327:Heart Block / Q000209:etiology / Q000503:physiopathology; D006329:Heart Conduction System / Q000503:physiopathology*; D007150:Immunohistochemistry; D008264:Macrophages / Q000737:chemistry / Q000166:cytology / Q000473:pathology; D020783:Matrix Metalloproteinase 7 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009203:Myocardial Infarction / Q000401:mortality* / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000737:chemistry / Q000473:pathology; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000166:cytology / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D016019:Survival Analysis; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D018031:Connexin 43; D011994:Recombinant Proteins; D020783:Matrix Metalloproteinase 7