title: CXCR3-independent actions of the CXC chemokine CXCL10 in the infarcted myocardium and in isolated cardiac fibroblasts are mediated through proteoglycans.
abstract: OBJECTIVE
  The CXC chemokine CXCL10 is 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.
  
  
  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)-β 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 of CXCL10 on cell migration.
  
  
  CONCLUSIONS
  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.
authors.affiliation: The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, 1300 Morris Park Avenue Forchheimer G46B, Bronx, NY 10461, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Saxena
authors.affiliation: Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Bujak
authors.affiliation: The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, 1300 Morris Park Avenue Forchheimer G46B, Bronx, NY 10461, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Frunza
authors.affiliation: The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, 1300 Morris Park Avenue Forchheimer G46B, Bronx, NY 10461, USA Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Dobaczewski
authors.affiliation: The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, 1300 Morris Park Avenue Forchheimer G46B, Bronx, NY 10461, USA Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Gonzalez-Quesada
authors.affiliation: Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Bao
authors.initials: B
authors.lastname: Lu
authors.affiliation: Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Gerard
authors.affiliation: The Wilf Family Cardiovascular Research Institute, Department of Medicine (Cardiology), Albert Einstein College of Medicine, 1300 Morris Park Avenue Forchheimer G46B, Bronx, NY 10461, USA Department of Medicine, Baylor College of Medicine, Houston, TX, USA nikolaos.frangogiannis@einstein.yu.edu.
authors.forename: Nikolaos G
authors.initials: NG
authors.lastname: Frangogiannis
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002469:Cell Separation / Q000379:methods; D054357:Chemokine CXCL10 / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D011509:Proteoglycans / Q000378:metabolism*; D054367:Receptors, CXCR3 / Q000378:metabolism*; D015398:Signal Transduction; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; C515188:Cxcr3 protein, mouse; D011509:Proteoglycans; D054367:Receptors, CXCR3
keywords: Cardiac remodeling; Chemokine; Fibroblast; Myocardial infarction; Proteoglycan