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Increased secretion of Gas6 by smooth muscle cells in human atherosclerotic carotid plaques

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
DOI: https://doi.org/10.1160/TH11-05-0368
Issue: 2012: 107/1 (Jan) pp. 1–199
Pages: 140-149

Increased secretion of Gas6 by smooth muscle cells in human atherosclerotic carotid plaques

Online Supplementary Material

S. Clauser (1, 2, 3), O. Meilhac (4, 5, 6), I. Bieche (7, 8), P. Raynal (9), P. Bruneval (8, 10, 11), J.-B. Michel (4, 5, 6), D. Borgel (1, 2)

(1) EA 4531, Université Paris-Sud, Châtenay-Malabry, France; (2) AP-HP, Hôpital Ambroise Paré, Boulogne-Billancourt, France; (3) Faculté de Médecine, Université de Versailles-Saint Quentin, Guyancourt, France; (4) INSERM U698, Paris, France; (5) AP-HP, CHU X-Bichat, Paris, France; (6) Université Paris Diderot, Paris, France; (7) INSERM UMR S745, Faculté de Pharmacie, Paris, France; (8) Université Paris Descartes, Paris, France; (9) Centre Hospitalier de Versailles, Le Chesnay, France; (10) INSERM U970, Paris, France; (11) AP-HP, Hôpital Européen Georges-Pompidou, Paris, France

Keywords

Atherosclerosis, GAS6, vascular smooth muscle cells, TGFβ

Summary

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.

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