title: Chemokines induce matrix metalloproteinase-2 through activation of epidermal growth factor receptor in arterial smooth muscle cells.
abstract: OBJECTIVE
  Matrix metalloproteinases (MMP) are critical to smooth muscle cell (SMC) migration in vivo. MMP-2 dysregulation has been implicated in the pathogenesis of abnormal arterial remodeling, aneurysm formation, and atherosclerotic plaque structure and stability. The chemokine receptors CCR3 and CXCR4 are present and functional on SMC and are up-regulated in vascular diseases such as atherosclerosis. We sought to determine a potential mechanism for chemokine receptor-mediated effects on the vasculature by asking whether the chemokines eotaxin (CCL11), the ligand for CCR3, and stromal cell-derived cell factor (SDF-1, CXCL12), the ligand for CXCR4, induce MMP-2 in SMC. Studies were then performed to define the signaling pathways involved.
  
  
  RESULTS
  As determined by RT-PCR, Western blotting and zymography, SDF-1 and eotaxin induce MMP-2 mRNA, protein, and activity in SMC. An anti-CCR3 antibody and a CXCR4 antagonist blocked proMMP-2 induction by SDF-1 and eotaxin, the respective ligands for the chemokine receptors CXCR4 and CCR3, suggesting that the inductions by these chemokines are receptor-mediated. Receptor cross-talk between G-protein-coupled receptors (GPCR) and the epidermal growth factor receptor (EGFR) is a method of expanding the GPCRs' signaling repertoire. We demonstrate, for the first time to our knowledge, that in SMC, chemokine induction of proMMP-2 is dependent on activation of the EGFR. Interestingly, by blocking the ligand binding domain of EGFR, we demonstrate that activation of EGFR by SDF-1 and eotaxin occurs through different cellular pathways.
  
  
  CONCLUSIONS
  The pro-inflammatory chemokines eotaxin and SDF induce proMMP-2 activation of EGFR through two different pathways. SDF and eotaxin, as regulators of proMMP-2 expression and by engaging in receptor cross-talk, may play critical roles in atherosclerosis, restenosis, and plaque rupture. These ligands and their respective receptors, CXCR4 and CCR3, therefore may serve as future potential therapeutic targets.
authors.affiliation: Zena and Michael A.Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kodali
authors.forename: Mustapha
authors.initials: M
authors.lastname: Hajjou
authors.forename: Adriane B
authors.initials: AB
authors.lastname: Berman
authors.forename: Meena B
authors.initials: MB
authors.lastname: Bansal
authors.forename: Shihong
authors.initials: S
authors.lastname: Zhang
authors.forename: Jiang Jin
authors.initials: JJ
authors.lastname: Pan
authors.forename: Alison D
authors.initials: AD
authors.lastname: Schecter
mesh_terms: D000818:Animals; D001158:Arteries; D050197:Atherosclerosis / Q000276:immunology*; D015153:Blotting, Western / Q000379:methods; D002478:Cells, Cultured; D054413:Chemokine CCL11; D054377:Chemokine CXCL12; D018925:Chemokines / Q000494:pharmacology*; D019742:Chemokines, CC / Q000494:pharmacology; D019743:Chemokines, CXC / Q000494:pharmacology; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
chemical_list: C515456:CCL11 protein, human; C515255:CXCL12 protein, human; C515457:Ccl11 protein, mouse; C515458:Ccl11 protein, rat; D054413:Chemokine CCL11; D054377:Chemokine CXCL12; D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D020778:Matrix Metalloproteinase 2