title: Increased secretion of Gas6 by smooth muscle cells in human atherosclerotic carotid plaques.
abstract: Vitamin K-dependent protein Gas6 (growth-arrest specific gene 6) plays a role in vascular smooth muscle cell (VSMC) survival and migration, as well as in endothelium and leukocyte activation, and could therefore be involved in atherosclerosis. However, the study of mouse models has led to contradictory results regarding the pro- or anti-atherogenic properties of Gas6, and relatively few data are available in human pathophysiology. To better understand the implication of Gas6 in human atherosclerosis, we studied Gas6 expression and secretion in vitro  in human VSMC, and analysed the effect of Gas6 on inflammatory gene expression in these cells. We show that Gas6 secretion in VSMC is strongly induced by the anti-inflammatory cytokine transforming growth factor (TGF)β, and that VSMC stimulation by recombinant Gas6 decreases the expression of inflammatory genes tumour necrosis factor (TNF)α and intracellular adhesion molecule (ICAM)-1. The study of Gas6 expression in human carotid endarterectomy samples revealed that Gas6 is mainly expressed by VSMC at all stages of human atherosclerosis, but is not detected in normal vessel wall. Analysis of plaque secretomes showed that Gas6 secretion is markedly higher in non-complicated plaques than in complicated plaques, and that TGFβ secretion pattern mirrors that of Gas6. We conclude that Gas6 is secreted in human atherosclerotic plaques by VSMC following stimulation by TGFβ, and that Gas6 secretion decreases with plaque complication. Therefore, we propose that Gas6 acts as a protective factor, in part by reducing the pro-inflammatory phenotype of VSMC.
authors.affiliation: EA 4531, Université Paris-Sud, Châtenay-Malabry, France. sylvain.clauser@apr.aphp.fr
authors.forename: Sylvain
authors.initials: S
authors.lastname: Clauser
authors.forename: Olivier
authors.initials: O
authors.lastname: Meilhac
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.forename: Pierre
authors.initials: P
authors.lastname: Raynal
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Michel
authors.forename: Delphine
authors.initials: D
authors.lastname: Borgel
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D002465:Cell Movement; D002470:Cell Survival; D004730:Endothelium, Vascular / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D010641:Phenotype; D058226:Plaque, Atherosclerotic / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D000893:Anti-Inflammatory Agents; D018799:Intercellular Adhesion Molecule-1; D036341:Intercellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D000099255:Growth Arrest-Specific Protein 6