A novel function of FoxO transcription factors in thrombin-stimulated vascular smooth muscle cell proliferation

Thrombosis and Haemostasis
Shailaja G MahajanBernhard H Rauch

Abstract

Thrombin exerts coagulation-independent effects on the proliferation and migration of vascular smooth muscle cells (SMC). Forkhead box-O (FoxO) transcription factors regulate cell proliferation, apoptosis and cell cycle arrest, but a possible functional interaction between thrombin and FoxO factors has not been identified to date. In human cultured vascular SMC, thrombin induced a time-dependent phosphorylation of FoxO1 and FoxO3 but not FoxO4. This effect was mimicked by an activating-peptide (AP) for protease-activated receptor (PAR)-1, and abolished by a PAR-1 antagonist (SCH79797). APs for other PARs were without effect. FoxO1 and FoxO3 phosphorylation were prevented by the PI3 kinase (PI3K) inhibitor LY294002 while inhibitors of ERK1/2 (PD98059) or p38MAPK (SB203580) were ineffective. LY294002 moreover prevented thrombin-stimulated SMC mitogenesis and proliferation. FoxO1 and FoxO3 siRNA augmented basal DNA synthesis and proliferation of SMC. Nuclear content of FoxO proteins decreased time-dependently in response to thrombin, coincided with suppressed expression of the cell cycle regulating genes p21CIP1 and p27kip1 by thrombin. FoxO1 siRNA reduced basal p21CIP1 while FoxO3 siRNA attenuated p27kip1 expression; thrombin did...Continue Reading

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Citations

May 26, 2012·Thrombosis and Haemostasis·Robert K Andrews
Oct 25, 2012·Thrombosis and Haemostasis·Hannah Lee, Justin R Hamilton
Nov 26, 2015·Mediators of Inflammation·Shailaja Mahajan-ThakurBernhard H Rauch
Feb 28, 2015·Arteriosclerosis, Thrombosis, and Vascular Biology·Karima Ait AissaVéronique Regnault
Jun 27, 2019·Journal of Cellular and Molecular Medicine·Mei ZhaoLing Lin
Dec 20, 2018·International Journal of Molecular Sciences·Chien-Chung YangChuen-Mao Yang

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