TY  - JOUR
A1  - Böhm, Andreas
A1  - Flößer, Anja
A1  - Ermler, Swen
A1  - Fender, Anke C.
A1  - Lüth, Anja
A1  - Kleuser, Burkhard
A1  - Schrör, Karsten
A1  - Rauch, Bernhard H.
T1  - Factor-Xa-induced mitogenesis and migration require sphingosine kinase activity and S1P formation in human vascular smooth muscle cells
JF  - Cardiovascular research
N2  - Sphingosine-1-phosphate (S1P) is a cellular signalling lipid generated by sphingosine kinase-1 (SPHK1). The aim of the study was to investigate whether the activated coagulation factor-X (FXa) regulates SPHK1 transcription and the formation of S1P and subsequent mitogenesis and migration of human vascular smooth muscle cells (SMC).
 FXa induced a time- (36 h) and concentration-dependent (330 nmol/L) increase of SPHK1 mRNA and protein expression in human aortic SMC, resulting in an increased synthesis of S1P. FXa-stimulated transcription of SPHK1 was mediated by the protease-activated receptor-1 (PAR-1) and PAR-2. In human carotid artery plaques, expression of SPHK1 was observed at SMC-rich sites and was co-localized with intraplaque FX/FXa content. FXa-induced SPHK1 transcription was attenuated by inhibitors of Rho kinase (Y27632) and by protein kinase C (PKC) isoforms (GF109203X). In addition, FXa rapidly induced the activation of the small GTPase Rho A. Inhibition of signalling pathways which regulate SPHK1 expression, inhibition of its activity or siRNA-mediated SPHK1 knockdown attenuated the mitogenic and chemotactic response of human SMC to FXa.
 These data suggest that FXa induces SPHK1 expression and increases S1P formation independent of thrombin and that this involves the activation of Rho A and PKC signalling. In addition to its key function in coagulation, this direct effect of FXa on human SMC may increase cell proliferation and migration at sites of vessel injury and thereby contribute to the progression of vascular lesions.
KW  - Factor-Xa
KW  - Atherosclerosis
KW  - Proliferation
KW  - Smooth muscle cells
KW  - Sphingosine kinase-1
Y1  - 2013
U6  - https://doi.org/10.1093/cvr/cvt112
SN  - 0008-6363
VL  - 99
IS  - 3
SP  - 505
EP  - 513
PB  - Oxford Univ. Press
CY  - Oxford
ER  -