Matrix Metalloproteinase-7 Affects Connexin-43 Levels, Electrical Conduction, and Survival After Myocardial Infarction

Authors:
  • GEG. Patricia Escobar
    G. Patricia Escobar
  • RMRupak Mukherjee
    Rupak Mukherjee
  • DGDanielle K. Goshorn
    Danielle K. Goshorn
  • NSNina J. Sheats
    Nina J. Sheats
  • JBJames A. Bruce
    James A. Bruce
  • IMI. Matthew Mains
    I. Matthew Mains
  • JHJennifer K. Hendrick
    Jennifer K. Hendrick
  • KHKenneth W. Hewett
    Kenneth W. Hewett
  • RGRobert G. Gourdie
    Robert G. Gourdie
  • LMLynn M. Matrisian
    Lynn M. Matrisian
  • FSFrancis G. Spinale
    Francis G. Spinale
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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. Methods and 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.

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