Critical role of monocyte chemoattractant protein-1/CC chemokine ligand 2 in the pathogenesis of ischemic cardiomyopathy

Nikolaos G. Frangogiannis, Oliver Dewald, Ying Xia, Guofeng Ren, Sandra Haudek, Thorsten Leucker, Daniela Kraemer, George Taffet, Barrett J. Rollins, Mark L. Entman

Research output: Contribution to journalArticle

159 Citations (Scopus)

Abstract

BACKGROUND - Cardiac interstitial fibrosis plays an important role in the pathogenesis of ischemic cardiomyopathy, contributing to systolic and diastolic dysfunction. We have recently developed a mouse model of fibrotic noninfarctive cardiomyopathy due to brief repetitive myocardial ischemia and reperfusion. In this model, fibrotic changes are preceded by marked and selective induction of the CC chemokine monocyte chemoattractant protein-1 (MCP-1). We hypothesized that MCP-1 may mediate fibrotic remodeling through recruitment of mononuclear cells and direct effects on fibroblasts. METHODS AND RESULTS - Wild-type (WT) and MCP-1-null mice underwent daily 15-minute coronary occlusions followed by reperfusion. Additional WT animals received intraperitoneal injections of a neutralizing anti-MCP-1 antibody after the end of each ischemic episode. Hearts were examined echocardiographically and processed for histological and RNA studies. WT mice undergoing repetitive brief myocardial ischemia and reperfusion protocols exhibited macrophage infiltration after 3 to 5 days and marked interstitial fibrosis in the ischemic area after 7 days, accompanied by ventricular dysfunction. MCP-1-null mice had markedly diminished interstitial fibrosis, lower macrophage infiltration, and attenuated ventricular dysfunction compared with WT animals. MCP-1 neutralization also inhibited interstitial fibrosis, decreasing left ventricular dysfunction and regional hypocontractility. Cardiac myofibroblasts isolated from WT but not from MCP-1-null animals undergoing repetitive myocardial ischemia and reperfusion demonstrated enhanced proliferative capacity. However, MCP-1 stimulation did not induce cardiac myofibroblast proliferation and did not alter expression of fibrosis-associated genes. CONCLUSIONS - Defective MCP-1 signaling inhibits the development of ischemic fibrotic cardiomyopathy in mice. The profibrotic actions of MCP-1 are associated with decreased macrophage recruitment and may not involve direct effects on cardiac fibroblasts.

Original languageEnglish (US)
Pages (from-to)584-592
Number of pages9
JournalCirculation
Volume115
Issue number5
DOIs
StatePublished - Feb 2007
Externally publishedYes

Fingerprint

CC Chemokines
Chemokine CCL2
Cardiomyopathies
Ligands
Fibrosis
Myocardial Reperfusion
Myocardial Ischemia
Ventricular Dysfunction
Wild Animals
Myofibroblasts
Macrophages
Fibroblasts
Coronary Occlusion
Left Ventricular Dysfunction
Intraperitoneal Injections
Reperfusion
RNA
Antibodies

Keywords

  • Cardiomyopathy
  • Fibrosis
  • Immunology
  • Inflammation
  • Ischemia
  • Pathology
  • Reperfusion

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Critical role of monocyte chemoattractant protein-1/CC chemokine ligand 2 in the pathogenesis of ischemic cardiomyopathy. / Frangogiannis, Nikolaos G.; Dewald, Oliver; Xia, Ying; Ren, Guofeng; Haudek, Sandra; Leucker, Thorsten; Kraemer, Daniela; Taffet, George; Rollins, Barrett J.; Entman, Mark L.

In: Circulation, Vol. 115, No. 5, 02.2007, p. 584-592.

Research output: Contribution to journalArticle

Frangogiannis, NG, Dewald, O, Xia, Y, Ren, G, Haudek, S, Leucker, T, Kraemer, D, Taffet, G, Rollins, BJ & Entman, ML 2007, 'Critical role of monocyte chemoattractant protein-1/CC chemokine ligand 2 in the pathogenesis of ischemic cardiomyopathy', Circulation, vol. 115, no. 5, pp. 584-592. https://doi.org/10.1161/CIRCULATIONAHA.106.646091
Frangogiannis, Nikolaos G. ; Dewald, Oliver ; Xia, Ying ; Ren, Guofeng ; Haudek, Sandra ; Leucker, Thorsten ; Kraemer, Daniela ; Taffet, George ; Rollins, Barrett J. ; Entman, Mark L. / Critical role of monocyte chemoattractant protein-1/CC chemokine ligand 2 in the pathogenesis of ischemic cardiomyopathy. In: Circulation. 2007 ; Vol. 115, No. 5. pp. 584-592.
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abstract = "BACKGROUND - Cardiac interstitial fibrosis plays an important role in the pathogenesis of ischemic cardiomyopathy, contributing to systolic and diastolic dysfunction. We have recently developed a mouse model of fibrotic noninfarctive cardiomyopathy due to brief repetitive myocardial ischemia and reperfusion. In this model, fibrotic changes are preceded by marked and selective induction of the CC chemokine monocyte chemoattractant protein-1 (MCP-1). We hypothesized that MCP-1 may mediate fibrotic remodeling through recruitment of mononuclear cells and direct effects on fibroblasts. METHODS AND RESULTS - Wild-type (WT) and MCP-1-null mice underwent daily 15-minute coronary occlusions followed by reperfusion. Additional WT animals received intraperitoneal injections of a neutralizing anti-MCP-1 antibody after the end of each ischemic episode. Hearts were examined echocardiographically and processed for histological and RNA studies. WT mice undergoing repetitive brief myocardial ischemia and reperfusion protocols exhibited macrophage infiltration after 3 to 5 days and marked interstitial fibrosis in the ischemic area after 7 days, accompanied by ventricular dysfunction. MCP-1-null mice had markedly diminished interstitial fibrosis, lower macrophage infiltration, and attenuated ventricular dysfunction compared with WT animals. MCP-1 neutralization also inhibited interstitial fibrosis, decreasing left ventricular dysfunction and regional hypocontractility. Cardiac myofibroblasts isolated from WT but not from MCP-1-null animals undergoing repetitive myocardial ischemia and reperfusion demonstrated enhanced proliferative capacity. However, MCP-1 stimulation did not induce cardiac myofibroblast proliferation and did not alter expression of fibrosis-associated genes. CONCLUSIONS - Defective MCP-1 signaling inhibits the development of ischemic fibrotic cardiomyopathy in mice. The profibrotic actions of MCP-1 are associated with decreased macrophage recruitment and may not involve direct effects on cardiac fibroblasts.",
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T1 - Critical role of monocyte chemoattractant protein-1/CC chemokine ligand 2 in the pathogenesis of ischemic cardiomyopathy

AU - Frangogiannis, Nikolaos G.

AU - Dewald, Oliver

AU - Xia, Ying

AU - Ren, Guofeng

AU - Haudek, Sandra

AU - Leucker, Thorsten

AU - Kraemer, Daniela

AU - Taffet, George

AU - Rollins, Barrett J.

AU - Entman, Mark L.

PY - 2007/2

Y1 - 2007/2

N2 - BACKGROUND - Cardiac interstitial fibrosis plays an important role in the pathogenesis of ischemic cardiomyopathy, contributing to systolic and diastolic dysfunction. We have recently developed a mouse model of fibrotic noninfarctive cardiomyopathy due to brief repetitive myocardial ischemia and reperfusion. In this model, fibrotic changes are preceded by marked and selective induction of the CC chemokine monocyte chemoattractant protein-1 (MCP-1). We hypothesized that MCP-1 may mediate fibrotic remodeling through recruitment of mononuclear cells and direct effects on fibroblasts. METHODS AND RESULTS - Wild-type (WT) and MCP-1-null mice underwent daily 15-minute coronary occlusions followed by reperfusion. Additional WT animals received intraperitoneal injections of a neutralizing anti-MCP-1 antibody after the end of each ischemic episode. Hearts were examined echocardiographically and processed for histological and RNA studies. WT mice undergoing repetitive brief myocardial ischemia and reperfusion protocols exhibited macrophage infiltration after 3 to 5 days and marked interstitial fibrosis in the ischemic area after 7 days, accompanied by ventricular dysfunction. MCP-1-null mice had markedly diminished interstitial fibrosis, lower macrophage infiltration, and attenuated ventricular dysfunction compared with WT animals. MCP-1 neutralization also inhibited interstitial fibrosis, decreasing left ventricular dysfunction and regional hypocontractility. Cardiac myofibroblasts isolated from WT but not from MCP-1-null animals undergoing repetitive myocardial ischemia and reperfusion demonstrated enhanced proliferative capacity. However, MCP-1 stimulation did not induce cardiac myofibroblast proliferation and did not alter expression of fibrosis-associated genes. CONCLUSIONS - Defective MCP-1 signaling inhibits the development of ischemic fibrotic cardiomyopathy in mice. The profibrotic actions of MCP-1 are associated with decreased macrophage recruitment and may not involve direct effects on cardiac fibroblasts.

AB - BACKGROUND - Cardiac interstitial fibrosis plays an important role in the pathogenesis of ischemic cardiomyopathy, contributing to systolic and diastolic dysfunction. We have recently developed a mouse model of fibrotic noninfarctive cardiomyopathy due to brief repetitive myocardial ischemia and reperfusion. In this model, fibrotic changes are preceded by marked and selective induction of the CC chemokine monocyte chemoattractant protein-1 (MCP-1). We hypothesized that MCP-1 may mediate fibrotic remodeling through recruitment of mononuclear cells and direct effects on fibroblasts. METHODS AND RESULTS - Wild-type (WT) and MCP-1-null mice underwent daily 15-minute coronary occlusions followed by reperfusion. Additional WT animals received intraperitoneal injections of a neutralizing anti-MCP-1 antibody after the end of each ischemic episode. Hearts were examined echocardiographically and processed for histological and RNA studies. WT mice undergoing repetitive brief myocardial ischemia and reperfusion protocols exhibited macrophage infiltration after 3 to 5 days and marked interstitial fibrosis in the ischemic area after 7 days, accompanied by ventricular dysfunction. MCP-1-null mice had markedly diminished interstitial fibrosis, lower macrophage infiltration, and attenuated ventricular dysfunction compared with WT animals. MCP-1 neutralization also inhibited interstitial fibrosis, decreasing left ventricular dysfunction and regional hypocontractility. Cardiac myofibroblasts isolated from WT but not from MCP-1-null animals undergoing repetitive myocardial ischemia and reperfusion demonstrated enhanced proliferative capacity. However, MCP-1 stimulation did not induce cardiac myofibroblast proliferation and did not alter expression of fibrosis-associated genes. CONCLUSIONS - Defective MCP-1 signaling inhibits the development of ischemic fibrotic cardiomyopathy in mice. The profibrotic actions of MCP-1 are associated with decreased macrophage recruitment and may not involve direct effects on cardiac fibroblasts.

KW - Cardiomyopathy

KW - Fibrosis

KW - Immunology

KW - Inflammation

KW - Ischemia

KW - Pathology

KW - Reperfusion

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DO - 10.1161/CIRCULATIONAHA.106.646091

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