title: S100B-RAGE dependent VEGF secretion by cardiac myocytes induces myofibroblast proliferation.
abstract: Post-infarct remodeling is associated with the upregulation of the receptor for advanced glycation end products (RAGE), the induction of its ligand the calcium binding protein S100B and the release of the potent endothelial-cell specific mitogen vascular endothelial growth factor (VEGF). To determine a possible functional interaction between S100B, RAGE and VEGF we stimulated rat neonatal cardiac myocyte cultures transfected with either RAGE or a dominant-negative cytoplasmic deletion mutant of RAGE with S100B for 48 h. Under baseline conditions, cardiac myocytes express low levels of RAGE and VEGF and secrete VEGF in the medium as measured by ELISA. In RAGE overexpressing myocytes, S100B (100 nM) resulted in increases in VEGF mRNA, VEGF protein, VEGF secretion, and activation of the transcription factor NF-κB. Pre-treatment of RAGE overexpressing myocytes with the NF-κB inhibitor caffeic acid phenethyl ester inhibited increases in VEGF mRNA, VEGF protein and VEGF in the medium by S100B. In myocytes expressing dominant-negative RAGE, S100B did not induce VEGF mRNA, VEGF protein, VEGF secretion or NF-κB activation. In culture, rat neonatal and adult cardiac fibroblasts undergo phenotypic transition to myofibroblasts. Treatment of neonatal and adult myofibroblasts with VEGF (10 ng/mL) induces VEGFR-2 (flk-1/KDR) tyrosine kinase phosphorylation, ERK1/2 phosphorylation and myofibroblast proliferation. Together these data demonstrate that secreted VEGF by cardiac myocytes in response to S100B via RAGE ligation induces myofibroblast proliferation potentially contributing to scar formation observed in infarcted myocardium. This article is part of a Special Issue entitled "Local Signaling in Myocytes".
authors: Division of Cardiology, Department of Medicine, Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. jimtsoporis@sympatico.ca
authors: James N
authors: JN
authors: Tsoporis
authors: Shehla
authors: S
authors: Izhar
authors: Gerald
authors: G
authors: Proteau
authors: Graham
authors: G
authors: Slaughter
authors: Thomas G
authors: TG
authors: Parker
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D058628:Myofibroblasts / Q000166:cytology / Q000187:drug effects*; D016328:NF-kappa B / Q000378:metabolism; D009414:Nerve Growth Factors / Q000097:blood / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000097:blood / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D020257:Ventricular Remodeling
chemical_list: D016328:NF-kappa B; D009414:Nerve Growth Factors; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579160:S100B protein, human; C579158:S100b protein, rat; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2