Matrix-dependent mechanism of neutrophil-mediated release and activation of matrix metalloproteinase 9 in myocardial ischemia/reperfusion

Merry L Lindsey, Kyle Wedin, Michael D. Brown, Christopher Keller, Alida J. Evans, James Smolen, Alan R. Burns, Roger D. Rossen, Lloyd Michael, Mark Entman

Research output: Contribution to journalArticle

172 Citations (Scopus)

Abstract

Background - A key component of reperfusion of myocardial infarction is an immediate inflammatory response, which enhances tissue repair. Matrix turnover is crucial to tissue repair, and matrix metalloproteinases (MMPs) are key enzymes involved in matrix degradation. The hypothesis tested is that one inflammation-based effector of tissue repair is the secretion and activation of MMP-9 by infiltrating neutrophils. Methods and Results - Cardiac lymph and tissue were assayed for latent and active MMP-2 and MMP-9 by zymography and immunochemistry. Dual-labeling immunofluorescence determined the cellular source of MMP-9 protein. Isolated canine neutrophils were incubated with preischemic and postischemic cardiac lymph in the presence and absence of collagen-fibronectin pads, and the supernatants were assayed for latent and active MMP-9. MMP-9 increased during the first hours of reperfusion in both lymph supernatants and myocardial extracts, and this increase was of neutrophil origin. MMP-9 in the cardiac lymph remained latent but was activatable. In contrast, MMP-9 in the myocardium was in both latent and active forms. In situ zymography demonstrated that activated MMP-9 surrounded the infiltrated neutrophils. When postischemic cardiac lymph was incubated with neutrophils in vitro, MMP-9 secretion and activation occurred only in the presence of a collagen-fibronectin substrate; preischemic cardiac lymph did not induce significant secretion or activation. Conclusions - Infiltrating neutrophils are an early source of MMP-9 after reperfusion, and a portion of MMP-9 in the myocardium is active. Infiltrating neutrophils may localize MMP-9 activation by secreting MMP-9 and as a source of activating proteases.

Original languageEnglish (US)
Pages (from-to)2181-2187
Number of pages7
JournalCirculation
Volume103
Issue number17
DOIs
StatePublished - May 1 2001

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Myocardial Reperfusion
Matrix Metalloproteinase 9
Myocardial Ischemia
Neutrophils
Lymph
Reperfusion
Fibronectins
Myocardium
Collagen
Immunochemistry
Matrix Metalloproteinase 2
Matrix Metalloproteinases
Fluorescent Antibody Technique
Canidae

Keywords

  • Blood cells
  • Ischemia
  • Metalloproteinases
  • Reperfusion

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Matrix-dependent mechanism of neutrophil-mediated release and activation of matrix metalloproteinase 9 in myocardial ischemia/reperfusion. / Lindsey, Merry L; Wedin, Kyle; Brown, Michael D.; Keller, Christopher; Evans, Alida J.; Smolen, James; Burns, Alan R.; Rossen, Roger D.; Michael, Lloyd; Entman, Mark.

In: Circulation, Vol. 103, No. 17, 01.05.2001, p. 2181-2187.

Research output: Contribution to journalArticle

Lindsey, ML, Wedin, K, Brown, MD, Keller, C, Evans, AJ, Smolen, J, Burns, AR, Rossen, RD, Michael, L & Entman, M 2001, 'Matrix-dependent mechanism of neutrophil-mediated release and activation of matrix metalloproteinase 9 in myocardial ischemia/reperfusion', Circulation, vol. 103, no. 17, pp. 2181-2187. https://doi.org/10.1161/01.CIR.103.17.2181
Lindsey, Merry L ; Wedin, Kyle ; Brown, Michael D. ; Keller, Christopher ; Evans, Alida J. ; Smolen, James ; Burns, Alan R. ; Rossen, Roger D. ; Michael, Lloyd ; Entman, Mark. / Matrix-dependent mechanism of neutrophil-mediated release and activation of matrix metalloproteinase 9 in myocardial ischemia/reperfusion. In: Circulation. 2001 ; Vol. 103, No. 17. pp. 2181-2187.
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T1 - Matrix-dependent mechanism of neutrophil-mediated release and activation of matrix metalloproteinase 9 in myocardial ischemia/reperfusion

AU - Lindsey, Merry L

AU - Wedin, Kyle

AU - Brown, Michael D.

AU - Keller, Christopher

AU - Evans, Alida J.

AU - Smolen, James

AU - Burns, Alan R.

AU - Rossen, Roger D.

AU - Michael, Lloyd

AU - Entman, Mark

PY - 2001/5/1

Y1 - 2001/5/1

N2 - Background - A key component of reperfusion of myocardial infarction is an immediate inflammatory response, which enhances tissue repair. Matrix turnover is crucial to tissue repair, and matrix metalloproteinases (MMPs) are key enzymes involved in matrix degradation. The hypothesis tested is that one inflammation-based effector of tissue repair is the secretion and activation of MMP-9 by infiltrating neutrophils. Methods and Results - Cardiac lymph and tissue were assayed for latent and active MMP-2 and MMP-9 by zymography and immunochemistry. Dual-labeling immunofluorescence determined the cellular source of MMP-9 protein. Isolated canine neutrophils were incubated with preischemic and postischemic cardiac lymph in the presence and absence of collagen-fibronectin pads, and the supernatants were assayed for latent and active MMP-9. MMP-9 increased during the first hours of reperfusion in both lymph supernatants and myocardial extracts, and this increase was of neutrophil origin. MMP-9 in the cardiac lymph remained latent but was activatable. In contrast, MMP-9 in the myocardium was in both latent and active forms. In situ zymography demonstrated that activated MMP-9 surrounded the infiltrated neutrophils. When postischemic cardiac lymph was incubated with neutrophils in vitro, MMP-9 secretion and activation occurred only in the presence of a collagen-fibronectin substrate; preischemic cardiac lymph did not induce significant secretion or activation. Conclusions - Infiltrating neutrophils are an early source of MMP-9 after reperfusion, and a portion of MMP-9 in the myocardium is active. Infiltrating neutrophils may localize MMP-9 activation by secreting MMP-9 and as a source of activating proteases.

AB - Background - A key component of reperfusion of myocardial infarction is an immediate inflammatory response, which enhances tissue repair. Matrix turnover is crucial to tissue repair, and matrix metalloproteinases (MMPs) are key enzymes involved in matrix degradation. The hypothesis tested is that one inflammation-based effector of tissue repair is the secretion and activation of MMP-9 by infiltrating neutrophils. Methods and Results - Cardiac lymph and tissue were assayed for latent and active MMP-2 and MMP-9 by zymography and immunochemistry. Dual-labeling immunofluorescence determined the cellular source of MMP-9 protein. Isolated canine neutrophils were incubated with preischemic and postischemic cardiac lymph in the presence and absence of collagen-fibronectin pads, and the supernatants were assayed for latent and active MMP-9. MMP-9 increased during the first hours of reperfusion in both lymph supernatants and myocardial extracts, and this increase was of neutrophil origin. MMP-9 in the cardiac lymph remained latent but was activatable. In contrast, MMP-9 in the myocardium was in both latent and active forms. In situ zymography demonstrated that activated MMP-9 surrounded the infiltrated neutrophils. When postischemic cardiac lymph was incubated with neutrophils in vitro, MMP-9 secretion and activation occurred only in the presence of a collagen-fibronectin substrate; preischemic cardiac lymph did not induce significant secretion or activation. Conclusions - Infiltrating neutrophils are an early source of MMP-9 after reperfusion, and a portion of MMP-9 in the myocardium is active. Infiltrating neutrophils may localize MMP-9 activation by secreting MMP-9 and as a source of activating proteases.

KW - Blood cells

KW - Ischemia

KW - Metalloproteinases

KW - Reperfusion

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