CCL2/monocyte chemoattractant protein-1 regulates inflammatory responses critical to healing myocardial infarcts

Oliver Dewald, Pawel Zymek, Kim Winkelmann, Anna Koerting, Guofeng Ren, Tareq Abou-Khamis, Lloyd H. Michael, Barrett J. Rollins, Mark L. Entman, Nikolaos G. Frangogiannis

Research output: Contribution to journalArticle

378 Citations (Scopus)

Abstract

The CC chemokine Monocyte Chemoattractant Protein (MCP)-1/CCL2 has potent mononuclear cell chemoattractant properties, modulates fibroblast and endothelial cell phenotype and may play an important role in wound healing. In order to examine whether MCP-1 critically regulates myocardial infarct healing, we studied the effects of MCP-1 gene disruption and antibody neutralization in a closed-chest model of reperfused murine myocardial infarction. MCP-1 -/- mice had decreased and delayed macrophage infiltration in the healing infarct and demonstrated delayed replacement of injured cardiomyocytes with granulation tissue. In contrast, the time course and density of neutrophil infiltration was similar in MCP-1 null and wild-type animals. MCP-1 -/- infarcts had decreased mRNA expression of the cytokines TNF-α, IL-1β, TGF-β2, -β3, and IL-10 and demonstrated defective macrophage differentiation evidenced by decreased Osteopontin-1 expression. MCP-1 deficiency diminished myofibroblast accumulation but did not significantly affect infarct angiogenesis. Despite showing delayed phagocytotic removal of dead cardiomyocytes, MCP-1-/- mice had attenuated left ventricular remodeling, but similar infarct size when compared with wild-type animals. MCP-1 antibody inhibition resulted in defects comparable with the pathological findings noted in infarcted MCP-1-/- animals without an effect on macrophage recruitment. MCP-1 has important effects on macrophage recruitment and activation, cytokine synthesis and myofibroblast accumulation in healing infarcts. Absence of MCP-1 results in attenuated post-infarction left ventricular remodeling, at the expense of a prolonged inflammatory phase and delayed replacement of injured cardiomyocytes with granulation tissue.

Original languageEnglish (US)
Pages (from-to)881-889
Number of pages9
JournalCirculation Research
Volume96
Issue number8
DOIs
StatePublished - Apr 29 2005
Externally publishedYes

Fingerprint

Chemokine CCL2
Myocardial Infarction
Cardiac Myocytes
Ventricular Remodeling
Wild Animals
Myofibroblasts
Granulation Tissue
Macrophages
Cytokines
Protein Deficiency
CC Chemokines
Osteopontin
Macrophage Activation
Neutrophil Infiltration
Antibodies
Chemotactic Factors
Interleukin-1
Interleukin-10
Wound Healing
Infarction

Keywords

  • Cytokines
  • Monocyte chemoattractant protein-1
  • Myocardial infarction
  • Myocardial inflammation
  • Pathology

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

CCL2/monocyte chemoattractant protein-1 regulates inflammatory responses critical to healing myocardial infarcts. / Dewald, Oliver; Zymek, Pawel; Winkelmann, Kim; Koerting, Anna; Ren, Guofeng; Abou-Khamis, Tareq; Michael, Lloyd H.; Rollins, Barrett J.; Entman, Mark L.; Frangogiannis, Nikolaos G.

In: Circulation Research, Vol. 96, No. 8, 29.04.2005, p. 881-889.

Research output: Contribution to journalArticle

Dewald, O, Zymek, P, Winkelmann, K, Koerting, A, Ren, G, Abou-Khamis, T, Michael, LH, Rollins, BJ, Entman, ML & Frangogiannis, NG 2005, 'CCL2/monocyte chemoattractant protein-1 regulates inflammatory responses critical to healing myocardial infarcts', Circulation Research, vol. 96, no. 8, pp. 881-889. https://doi.org/10.1161/01.RES.0000163017.13772.3a
Dewald, Oliver ; Zymek, Pawel ; Winkelmann, Kim ; Koerting, Anna ; Ren, Guofeng ; Abou-Khamis, Tareq ; Michael, Lloyd H. ; Rollins, Barrett J. ; Entman, Mark L. ; Frangogiannis, Nikolaos G. / CCL2/monocyte chemoattractant protein-1 regulates inflammatory responses critical to healing myocardial infarcts. In: Circulation Research. 2005 ; Vol. 96, No. 8. pp. 881-889.
@article{0549be158ac9404ba8623f992a9afd01,
title = "CCL2/monocyte chemoattractant protein-1 regulates inflammatory responses critical to healing myocardial infarcts",
abstract = "The CC chemokine Monocyte Chemoattractant Protein (MCP)-1/CCL2 has potent mononuclear cell chemoattractant properties, modulates fibroblast and endothelial cell phenotype and may play an important role in wound healing. In order to examine whether MCP-1 critically regulates myocardial infarct healing, we studied the effects of MCP-1 gene disruption and antibody neutralization in a closed-chest model of reperfused murine myocardial infarction. MCP-1 -/- mice had decreased and delayed macrophage infiltration in the healing infarct and demonstrated delayed replacement of injured cardiomyocytes with granulation tissue. In contrast, the time course and density of neutrophil infiltration was similar in MCP-1 null and wild-type animals. MCP-1 -/- infarcts had decreased mRNA expression of the cytokines TNF-α, IL-1β, TGF-β2, -β3, and IL-10 and demonstrated defective macrophage differentiation evidenced by decreased Osteopontin-1 expression. MCP-1 deficiency diminished myofibroblast accumulation but did not significantly affect infarct angiogenesis. Despite showing delayed phagocytotic removal of dead cardiomyocytes, MCP-1-/- mice had attenuated left ventricular remodeling, but similar infarct size when compared with wild-type animals. MCP-1 antibody inhibition resulted in defects comparable with the pathological findings noted in infarcted MCP-1-/- animals without an effect on macrophage recruitment. MCP-1 has important effects on macrophage recruitment and activation, cytokine synthesis and myofibroblast accumulation in healing infarcts. Absence of MCP-1 results in attenuated post-infarction left ventricular remodeling, at the expense of a prolonged inflammatory phase and delayed replacement of injured cardiomyocytes with granulation tissue.",
keywords = "Cytokines, Monocyte chemoattractant protein-1, Myocardial infarction, Myocardial inflammation, Pathology",
author = "Oliver Dewald and Pawel Zymek and Kim Winkelmann and Anna Koerting and Guofeng Ren and Tareq Abou-Khamis and Michael, {Lloyd H.} and Rollins, {Barrett J.} and Entman, {Mark L.} and Frangogiannis, {Nikolaos G.}",
year = "2005",
month = "4",
day = "29",
doi = "10.1161/01.RES.0000163017.13772.3a",
language = "English (US)",
volume = "96",
pages = "881--889",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "8",

}

TY - JOUR

T1 - CCL2/monocyte chemoattractant protein-1 regulates inflammatory responses critical to healing myocardial infarcts

AU - Dewald, Oliver

AU - Zymek, Pawel

AU - Winkelmann, Kim

AU - Koerting, Anna

AU - Ren, Guofeng

AU - Abou-Khamis, Tareq

AU - Michael, Lloyd H.

AU - Rollins, Barrett J.

AU - Entman, Mark L.

AU - Frangogiannis, Nikolaos G.

PY - 2005/4/29

Y1 - 2005/4/29

N2 - The CC chemokine Monocyte Chemoattractant Protein (MCP)-1/CCL2 has potent mononuclear cell chemoattractant properties, modulates fibroblast and endothelial cell phenotype and may play an important role in wound healing. In order to examine whether MCP-1 critically regulates myocardial infarct healing, we studied the effects of MCP-1 gene disruption and antibody neutralization in a closed-chest model of reperfused murine myocardial infarction. MCP-1 -/- mice had decreased and delayed macrophage infiltration in the healing infarct and demonstrated delayed replacement of injured cardiomyocytes with granulation tissue. In contrast, the time course and density of neutrophil infiltration was similar in MCP-1 null and wild-type animals. MCP-1 -/- infarcts had decreased mRNA expression of the cytokines TNF-α, IL-1β, TGF-β2, -β3, and IL-10 and demonstrated defective macrophage differentiation evidenced by decreased Osteopontin-1 expression. MCP-1 deficiency diminished myofibroblast accumulation but did not significantly affect infarct angiogenesis. Despite showing delayed phagocytotic removal of dead cardiomyocytes, MCP-1-/- mice had attenuated left ventricular remodeling, but similar infarct size when compared with wild-type animals. MCP-1 antibody inhibition resulted in defects comparable with the pathological findings noted in infarcted MCP-1-/- animals without an effect on macrophage recruitment. MCP-1 has important effects on macrophage recruitment and activation, cytokine synthesis and myofibroblast accumulation in healing infarcts. Absence of MCP-1 results in attenuated post-infarction left ventricular remodeling, at the expense of a prolonged inflammatory phase and delayed replacement of injured cardiomyocytes with granulation tissue.

AB - The CC chemokine Monocyte Chemoattractant Protein (MCP)-1/CCL2 has potent mononuclear cell chemoattractant properties, modulates fibroblast and endothelial cell phenotype and may play an important role in wound healing. In order to examine whether MCP-1 critically regulates myocardial infarct healing, we studied the effects of MCP-1 gene disruption and antibody neutralization in a closed-chest model of reperfused murine myocardial infarction. MCP-1 -/- mice had decreased and delayed macrophage infiltration in the healing infarct and demonstrated delayed replacement of injured cardiomyocytes with granulation tissue. In contrast, the time course and density of neutrophil infiltration was similar in MCP-1 null and wild-type animals. MCP-1 -/- infarcts had decreased mRNA expression of the cytokines TNF-α, IL-1β, TGF-β2, -β3, and IL-10 and demonstrated defective macrophage differentiation evidenced by decreased Osteopontin-1 expression. MCP-1 deficiency diminished myofibroblast accumulation but did not significantly affect infarct angiogenesis. Despite showing delayed phagocytotic removal of dead cardiomyocytes, MCP-1-/- mice had attenuated left ventricular remodeling, but similar infarct size when compared with wild-type animals. MCP-1 antibody inhibition resulted in defects comparable with the pathological findings noted in infarcted MCP-1-/- animals without an effect on macrophage recruitment. MCP-1 has important effects on macrophage recruitment and activation, cytokine synthesis and myofibroblast accumulation in healing infarcts. Absence of MCP-1 results in attenuated post-infarction left ventricular remodeling, at the expense of a prolonged inflammatory phase and delayed replacement of injured cardiomyocytes with granulation tissue.

KW - Cytokines

KW - Monocyte chemoattractant protein-1

KW - Myocardial infarction

KW - Myocardial inflammation

KW - Pathology

UR - http://www.scopus.com/inward/record.url?scp=20944449211&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20944449211&partnerID=8YFLogxK

U2 - 10.1161/01.RES.0000163017.13772.3a

DO - 10.1161/01.RES.0000163017.13772.3a

M3 - Article

C2 - 15774854

AN - SCOPUS:20944449211

VL - 96

SP - 881

EP - 889

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 8

ER -