Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction

Merry L Lindsey, G. Patricia Escobar, Rupak Mukherjee, Danielle K. Goshorn, Nina J. Sheats, James A. Bruce, I. Matthew Mains, Jennifer K. Hendrick, Kenneth W. Hewett, Robert G. Gourdie, Lynn M. Matrisian, 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.

Original languageEnglish (US)
Pages (from-to)2919-2928
Number of pages10
JournalCirculation
Volume113
Issue number25
DOIs
StatePublished - Jun 1 2006

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Matrix Metalloproteinase 7
Connexin 43
Myocardial Infarction
Matrix Metalloproteinases
Connexins
Ventricular Remodeling
Surface Plasmon Resonance
Cardiac Myocytes
Computer Simulation

Keywords

  • Infarction
  • Leukocytes
  • Metalloproteinases
  • Myocardial infarction
  • Remodeling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Lindsey, M. L., Escobar, G. P., Mukherjee, R., Goshorn, D. K., Sheats, N. J., Bruce, J. A., ... Spinale, F. G. (2006). Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction. Circulation, 113(25), 2919-2928. https://doi.org/10.1161/CIRCULATIONAHA.106.612960

Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction. / Lindsey, Merry L; Escobar, G. Patricia; Mukherjee, Rupak; Goshorn, Danielle K.; Sheats, Nina J.; Bruce, James A.; Mains, I. Matthew; Hendrick, Jennifer K.; Hewett, Kenneth W.; Gourdie, Robert G.; Matrisian, Lynn M.; Spinale, Francis G.

In: Circulation, Vol. 113, No. 25, 01.06.2006, p. 2919-2928.

Research output: Contribution to journalArticle

Lindsey, ML, Escobar, GP, Mukherjee, R, Goshorn, DK, Sheats, NJ, Bruce, JA, Mains, IM, Hendrick, JK, Hewett, KW, Gourdie, RG, Matrisian, LM & Spinale, FG 2006, 'Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction', Circulation, vol. 113, no. 25, pp. 2919-2928. https://doi.org/10.1161/CIRCULATIONAHA.106.612960
Lindsey, Merry L ; Escobar, G. Patricia ; Mukherjee, Rupak ; Goshorn, Danielle K. ; Sheats, Nina J. ; Bruce, James A. ; Mains, I. Matthew ; Hendrick, Jennifer K. ; Hewett, Kenneth W. ; Gourdie, Robert G. ; Matrisian, Lynn M. ; Spinale, Francis G. / Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction. In: Circulation. 2006 ; Vol. 113, No. 25. pp. 2919-2928.
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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.",
keywords = "Infarction, Leukocytes, Metalloproteinases, Myocardial infarction, Remodeling",
author = "Lindsey, {Merry L} and Escobar, {G. Patricia} and Rupak Mukherjee and Goshorn, {Danielle K.} and Sheats, {Nina J.} and Bruce, {James A.} and Mains, {I. Matthew} and Hendrick, {Jennifer K.} and Hewett, {Kenneth W.} and Gourdie, {Robert G.} and Matrisian, {Lynn M.} and Spinale, {Francis G.}",
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T1 - Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction

AU - Lindsey, Merry L

AU - Escobar, G. Patricia

AU - Mukherjee, Rupak

AU - Goshorn, Danielle K.

AU - Sheats, Nina J.

AU - Bruce, James A.

AU - Mains, I. Matthew

AU - Hendrick, Jennifer K.

AU - Hewett, Kenneth W.

AU - Gourdie, Robert G.

AU - Matrisian, Lynn M.

AU - Spinale, Francis G.

PY - 2006/6/1

Y1 - 2006/6/1

N2 - 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.

AB - 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.

KW - Infarction

KW - Leukocytes

KW - Metalloproteinases

KW - Myocardial infarction

KW - Remodeling

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DO - 10.1161/CIRCULATIONAHA.106.612960

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JO - Circulation

JF - Circulation

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