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Growth arrest-specific 6 regulates thrombin-induced expression of vascular cell adhesion molecule-1 through forkhead box O1 in endothelial cells.
Bertin, F R; Lemarié, C A; Robins, R S; Blostein, M D.
Afiliación
  • Bertin FR; Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada.
  • Lemarié CA; Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada.
  • Robins RS; Department of Medicine, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
  • Blostein MD; The Royal Victoria Hospital, McGill University Health Center, McGill University, Montreal, Quebec, Canada.
J Thromb Haemost ; 13(12): 2260-72, 2015 Dec.
Article en En | MEDLINE | ID: mdl-26414399
BACKGROUND: Growth arrest-specific 6 (Gas6)-deficient mice are protected against venous thromboembolism (VTE), suggesting a role for Gas6 in this disorder. We previously demonstrated that Gas6 induces forkhead box O1 (FoxO-1) phosphorylation through the phosphoinositide 3-kinase-Akt pathway. FoxO-1 regulates the expression of vascular cell adhesion molecule-1 (VCAM-1), a molecule that has been implicated in VTE. OBJECTIVES: To assess the role of FoxO-1 in Gas6-dependent VCAM-1 expression. METHODS: Thrombin was used to stimulate endothelial cells (ECs). Wild-type (WT) and Gas6(-/-) ECs were transfected with small interfering RNA targeting Axl or FoxO-1, a luciferase-coupled plasmid containing the FoxO-1 consensus sequence, and a phosphorylation-resistant FoxO-1 mutant, or treated with an Akt inhibitor. VCAM-1 mRNA expression was measured by real time-qPCR. VCAM-1 protein expression and FoxO-1 and Akt phosphorylation were assessed by western blot analysis. FoxO-1 localization was assessed by immunofluorescence. Adhesion of bone marrow mononuclear cells (BM-MCs) on ECs was assessed by fluorescence. RESULTS AND CONCLUSIONS: Thrombin induces both VCAM-1 expression and FoxO-1 phosphorylation and nuclear exclusion in WT ECs only. Silencing of FoxO-1 enhances VCAM-1 expression in both WT and Gas6(-/-) ECs. Inhibition of Akt or FoxO-1 phosphorylation prevents VCAM-1 expression in WT ECs. These data show that Gas6 induces FoxO-1 phosphorylation, leading to derepression of VCAM-1 expression. BM-MC-EC adhesion is increased by thrombin in WT ECs. BM-MC-EC adhesion is further increased when FoxO-1 is silenced, but decreased when FoxO-1 phosphorylation is inhibited. These results demonstrate that the Gas6-FoxO-1 signaling axis plays an important role in VCAM-1 expression in the context of VTE by promoting BM-MC-EC adhesion.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Trombina / Molécula 1 de Adhesión Celular Vascular / Péptidos y Proteínas de Señalización Intercelular / Células Endoteliales / Factores de Transcripción Forkhead Límite: Animals Idioma: En Revista: J Thromb Haemost Asunto de la revista: HEMATOLOGIA Año: 2015 Tipo del documento: Article País de afiliación: Canadá

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Trombina / Molécula 1 de Adhesión Celular Vascular / Péptidos y Proteínas de Señalización Intercelular / Células Endoteliales / Factores de Transcripción Forkhead Límite: Animals Idioma: En Revista: J Thromb Haemost Asunto de la revista: HEMATOLOGIA Año: 2015 Tipo del documento: Article País de afiliación: Canadá