Induction of the CXC chemokine interferon-γ-inducible protein 10 regulates the reparative response following myocardial infarction

Marcin Bujak, Marcin Dobaczewski, Carlos Gonzalez-Quesada, Ying Xia, Thorsten Leucker, Pawel Zymek, Vikas Veeranna, Andrew M. Tager, Andrew D. Luster, Nikolaos G. Frangogiannis

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

Rationale: Interferon-γ-inducible protein (IP)-10/CXCL10, an angiostatic and antifibrotic chemokine with an important role in T-cell trafficking, is markedly induced in myocardial infarcts, and may regulate the reparative response. Objective: To study the role of IP-10 in cardiac repair and remodeling. Methods and Results: We studied cardiac repair in IP-10-null and wild-type (WT) mice undergoing reperfused infarction protocols and examined the effects of IP-10 on cardiac fibroblast function. IP-10-deficient and WT animals had comparable acute infarct size. However, the absence of IP-10 resulted in a hypercellular early reparative response and delayed contraction of the scar. Infarcted IP-10 -/- hearts exhibited accentuated early dilation, followed by rapid wall thinning during infarct maturation associated with systolic dysfunction. Although IP-10-null and WT mice had comparable cytokine expression, the absence of IP-10 was associated with marked alterations in the cellular content of the infarct. IP-10 -/- infarcts had more intense infiltration with CD45 + leukocytes, Mac-2 + macrophages, and α-smooth muscle actin (α-SMA) + myofibroblasts than WT infarcts but exhibited reduced recruitment of the subpopulations of leukocytes, T lymphocytes and α-SMA + cells that expressed CXCR3, the IP-10 receptor. IP-10 did not modulate cardiac fibroblast proliferation and apoptosis but significantly inhibited basic fibroblast growth factor-induced fibroblast migration. In addition, IP-10 enhanced growth factor-mediated wound contraction in fibroblast-populated collagen lattices. Conclusions: Endogenous IP-10 is an essential inhibitory signal that regulates the cellular composition of the healing infarct and promotes wound contraction, attenuating adverse remodeling. IP-10-mediated actions may be due, at least in part, to direct effects on fibroblast migration and function.

Original languageEnglish (US)
Pages (from-to)973-983
Number of pages11
JournalCirculation Research
Volume105
Issue number10
DOIs
StatePublished - Nov 2009
Externally publishedYes

Fingerprint

Chemokine CXCL10
CXC Chemokines
Myocardial Infarction
Proteins
Fibroblasts
Leukocytes
T-Lymphocytes
Wild Animals
Myofibroblasts
Wounds and Injuries
Fibroblast Growth Factor 2

Keywords

  • Chemokines
  • Fibrosis
  • Infarction
  • Remodeling
  • Wound healing

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Induction of the CXC chemokine interferon-γ-inducible protein 10 regulates the reparative response following myocardial infarction. / Bujak, Marcin; Dobaczewski, Marcin; Gonzalez-Quesada, Carlos; Xia, Ying; Leucker, Thorsten; Zymek, Pawel; Veeranna, Vikas; Tager, Andrew M.; Luster, Andrew D.; Frangogiannis, Nikolaos G.

In: Circulation Research, Vol. 105, No. 10, 11.2009, p. 973-983.

Research output: Contribution to journalArticle

Bujak, M, Dobaczewski, M, Gonzalez-Quesada, C, Xia, Y, Leucker, T, Zymek, P, Veeranna, V, Tager, AM, Luster, AD & Frangogiannis, NG 2009, 'Induction of the CXC chemokine interferon-γ-inducible protein 10 regulates the reparative response following myocardial infarction', Circulation Research, vol. 105, no. 10, pp. 973-983. https://doi.org/10.1161/CIRCRESAHA.109.199471
Bujak, Marcin ; Dobaczewski, Marcin ; Gonzalez-Quesada, Carlos ; Xia, Ying ; Leucker, Thorsten ; Zymek, Pawel ; Veeranna, Vikas ; Tager, Andrew M. ; Luster, Andrew D. ; Frangogiannis, Nikolaos G. / Induction of the CXC chemokine interferon-γ-inducible protein 10 regulates the reparative response following myocardial infarction. In: Circulation Research. 2009 ; Vol. 105, No. 10. pp. 973-983.
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abstract = "Rationale: Interferon-γ-inducible protein (IP)-10/CXCL10, an angiostatic and antifibrotic chemokine with an important role in T-cell trafficking, is markedly induced in myocardial infarcts, and may regulate the reparative response. Objective: To study the role of IP-10 in cardiac repair and remodeling. Methods and Results: We studied cardiac repair in IP-10-null and wild-type (WT) mice undergoing reperfused infarction protocols and examined the effects of IP-10 on cardiac fibroblast function. IP-10-deficient and WT animals had comparable acute infarct size. However, the absence of IP-10 resulted in a hypercellular early reparative response and delayed contraction of the scar. Infarcted IP-10 -/- hearts exhibited accentuated early dilation, followed by rapid wall thinning during infarct maturation associated with systolic dysfunction. Although IP-10-null and WT mice had comparable cytokine expression, the absence of IP-10 was associated with marked alterations in the cellular content of the infarct. IP-10 -/- infarcts had more intense infiltration with CD45 + leukocytes, Mac-2 + macrophages, and α-smooth muscle actin (α-SMA) + myofibroblasts than WT infarcts but exhibited reduced recruitment of the subpopulations of leukocytes, T lymphocytes and α-SMA + cells that expressed CXCR3, the IP-10 receptor. IP-10 did not modulate cardiac fibroblast proliferation and apoptosis but significantly inhibited basic fibroblast growth factor-induced fibroblast migration. In addition, IP-10 enhanced growth factor-mediated wound contraction in fibroblast-populated collagen lattices. Conclusions: Endogenous IP-10 is an essential inhibitory signal that regulates the cellular composition of the healing infarct and promotes wound contraction, attenuating adverse remodeling. IP-10-mediated actions may be due, at least in part, to direct effects on fibroblast migration and function.",
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AU - Bujak, Marcin

AU - Dobaczewski, Marcin

AU - Gonzalez-Quesada, Carlos

AU - Xia, Ying

AU - Leucker, Thorsten

AU - Zymek, Pawel

AU - Veeranna, Vikas

AU - Tager, Andrew M.

AU - Luster, Andrew D.

AU - Frangogiannis, Nikolaos G.

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N2 - Rationale: Interferon-γ-inducible protein (IP)-10/CXCL10, an angiostatic and antifibrotic chemokine with an important role in T-cell trafficking, is markedly induced in myocardial infarcts, and may regulate the reparative response. Objective: To study the role of IP-10 in cardiac repair and remodeling. Methods and Results: We studied cardiac repair in IP-10-null and wild-type (WT) mice undergoing reperfused infarction protocols and examined the effects of IP-10 on cardiac fibroblast function. IP-10-deficient and WT animals had comparable acute infarct size. However, the absence of IP-10 resulted in a hypercellular early reparative response and delayed contraction of the scar. Infarcted IP-10 -/- hearts exhibited accentuated early dilation, followed by rapid wall thinning during infarct maturation associated with systolic dysfunction. Although IP-10-null and WT mice had comparable cytokine expression, the absence of IP-10 was associated with marked alterations in the cellular content of the infarct. IP-10 -/- infarcts had more intense infiltration with CD45 + leukocytes, Mac-2 + macrophages, and α-smooth muscle actin (α-SMA) + myofibroblasts than WT infarcts but exhibited reduced recruitment of the subpopulations of leukocytes, T lymphocytes and α-SMA + cells that expressed CXCR3, the IP-10 receptor. IP-10 did not modulate cardiac fibroblast proliferation and apoptosis but significantly inhibited basic fibroblast growth factor-induced fibroblast migration. In addition, IP-10 enhanced growth factor-mediated wound contraction in fibroblast-populated collagen lattices. Conclusions: Endogenous IP-10 is an essential inhibitory signal that regulates the cellular composition of the healing infarct and promotes wound contraction, attenuating adverse remodeling. IP-10-mediated actions may be due, at least in part, to direct effects on fibroblast migration and function.

AB - Rationale: Interferon-γ-inducible protein (IP)-10/CXCL10, an angiostatic and antifibrotic chemokine with an important role in T-cell trafficking, is markedly induced in myocardial infarcts, and may regulate the reparative response. Objective: To study the role of IP-10 in cardiac repair and remodeling. Methods and Results: We studied cardiac repair in IP-10-null and wild-type (WT) mice undergoing reperfused infarction protocols and examined the effects of IP-10 on cardiac fibroblast function. IP-10-deficient and WT animals had comparable acute infarct size. However, the absence of IP-10 resulted in a hypercellular early reparative response and delayed contraction of the scar. Infarcted IP-10 -/- hearts exhibited accentuated early dilation, followed by rapid wall thinning during infarct maturation associated with systolic dysfunction. Although IP-10-null and WT mice had comparable cytokine expression, the absence of IP-10 was associated with marked alterations in the cellular content of the infarct. IP-10 -/- infarcts had more intense infiltration with CD45 + leukocytes, Mac-2 + macrophages, and α-smooth muscle actin (α-SMA) + myofibroblasts than WT infarcts but exhibited reduced recruitment of the subpopulations of leukocytes, T lymphocytes and α-SMA + cells that expressed CXCR3, the IP-10 receptor. IP-10 did not modulate cardiac fibroblast proliferation and apoptosis but significantly inhibited basic fibroblast growth factor-induced fibroblast migration. In addition, IP-10 enhanced growth factor-mediated wound contraction in fibroblast-populated collagen lattices. Conclusions: Endogenous IP-10 is an essential inhibitory signal that regulates the cellular composition of the healing infarct and promotes wound contraction, attenuating adverse remodeling. IP-10-mediated actions may be due, at least in part, to direct effects on fibroblast migration and function.

KW - Chemokines

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KW - Remodeling

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