CXCR3-independent actions of theCXCchemokine CXCL10in the infarctedmyocardium and in isolated cardiac fibroblasts are mediated through proteoglycans

Amit Saxena, Marcin Bujak, Olga Frunza, Marcin Dobaczewski, Carlos Gonzalez-Quesada, Bao Lu, Craig Gerard, Nikolaos G. Frangogiannis

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Aims TheCXCchemokineCXCL10is up-regulated in the infarcted myocardium and limits cardiac fibrosis by inhibiting growth factor-mediated fibroblast migration. CXCL10 signals by binding to its receptor CXCR3; however, recently CXCR3- independent CXCL10 actions have been suggested. Our study explores the role of CXCR3 signalling in myocardial infarction and investigates its involvement in mediating the anti-fibrotic effects of CXCL10. Methods and results Wild-type and CXCR3 null mice underwent reperfused infarction protocols. CXCL10 was markedly induced in the infarct; in contrast, expression of the other two CXCR3 ligands, CXCL9 and CXCL11 was extremely low. CXCR3 loss did not affect scar size, geometric ventricular remodelling, collagen deposition, and systolic dysfunction of the infarcted heart. CXCR3 null mice had increased peak neutrophil recruitment and delayed myofibroblast infiltration in the infarcted heart, but exhibited comparable myocardial expression of pro-inflammatory cytokines and chemokines. In vitro, CXCL10 did not modulate Transforming Growth Factor (TGF)-b signalling, but inhibited basic fibroblast growth factor (bFGF)-induced cardiac fibroblast migration in both wild-type and CXCR3 null cells. Treatment of fibroblasts with heparinase and chondroitinase to cleave glycosaminoglycan chains abrogated the inhibitory effects ofCXCL10 on cell migration. Conclusion CXCR3 signalling does not critically regulate cardiac remodelling and dysfunction following myocardial infarction. The anti-fibrotic effects of CXCL10 in the healing infarct and in isolated cardiac fibroblasts are CXCR3-independent and may be mediated through proteoglycan signalling. Thus, administration of CXCR3-defective forms of CXCL10 may be an effective anti-fibrotic strategy in the remodelling myocardium without activating a potentially injurious, CXCR3-driven T cell response.

Original languageEnglish (US)
Pages (from-to)217-227
Number of pages11
JournalCardiovascular research
Issue number2
StatePublished - Jul 15 2014


  • Cardiac remodeling
  • Chemokine
  • Fibroblast
  • Myocardial infarction
  • Proteoglycan

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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