EA 4531, Université Paris-Sud, Châtenay-Malabry, France.
Thromb Haemost. 2012 Jan;107(1):140-9. doi: 10.1160/TH11-05-0368. Epub 2011 Nov 10.
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.
维生素 K 依赖性蛋白 Gas6（生长停滞特异性基因 6）在血管平滑肌细胞（VSMC）存活和迁移，以及内皮细胞和白细胞激活中发挥作用，因此可能与动脉粥样硬化有关。然而，对小鼠模型的研究导致了关于 Gas6 的促动脉粥样硬化或抗动脉粥样硬化特性的矛盾结果，并且在人类病理生理学中相对较少的数据可用。为了更好地理解 Gas6 在人类动脉粥样硬化中的作用，我们在体外研究了人 VSMC 中 Gas6 的表达和分泌，并分析了 Gas6 对这些细胞中炎症基因表达的影响。我们表明，抗炎细胞因子转化生长因子 (TGF)β强烈诱导 VSMC 中 Gas6 的分泌，重组 Gas6 刺激 VSMC 可降低炎症基因肿瘤坏死因子 (TNF)α和细胞间黏附分子 (ICAM)-1 的表达。对人类颈动脉内膜切除术样本中 Gas6 表达的研究表明，Gas6 主要由人动脉粥样硬化各个阶段的 VSMC 表达，但在正常血管壁中未检测到。斑块分泌组学分析表明，非复杂斑块中 Gas6 的分泌明显高于复杂斑块，TGFβ的分泌模式与 Gas6 相似。我们得出结论，Gas6 是由 TGFβ刺激的人动脉粥样硬化斑块中的 VSMC 分泌的，并且随着斑块复杂性的增加，Gas6 的分泌减少。因此，我们提出 Gas6 作为一种保护因子，部分通过减少 VSMC 的促炎表型起作用。
