Sphingosine-1-phosphate induces COX-2 expression via PI3K/Akt and p42/p44 MAPK pathways in rat vascular smooth muscle cells
Article first published online: 28 FEB 2006
Copyright © 2006 Wiley-Liss, Inc.
Journal of Cellular Physiology
Volume 207, Issue 3, pages 757–766, June 2006
How to Cite
Hsieh, H.-L., Wu, C.-B., Sun, C.-C., Liao, C.-H., Lau, Y.-T. and Yang, C.-M. (2006), Sphingosine-1-phosphate induces COX-2 expression via PI3K/Akt and p42/p44 MAPK pathways in rat vascular smooth muscle cells. J. Cell. Physiol., 207: 757–766. doi: 10.1002/jcp.20621
- Issue published online: 28 MAR 2006
- Article first published online: 28 FEB 2006
- Manuscript Accepted: 10 JAN 2006
- Manuscript Received: 26 NOV 2005
- National Science Council, Taiwan. Grant Number: NSC94-2320-B-182-003
- Chang Gung Medical Research Foundation. Grant Number: CMRP-1371
Sphingosine 1-phosphate (S1P) has been shown to regulate smooth muscle cell proliferation, migration, and vascular maturation. S1P increases the expression of several proteins including COX-2 in vascular smooth muscle cells (VSMCs) and contributes to arteriosclerosis. However, the mechanisms regulating COX-2 expression by S1P in VSMCs remain unclear. Western blotting and RT-PCR analyses showed that S1P induced the expression of COX-2 mRNA and protein in a time- and concentration-dependent manner, which was attenuated by inhibitors of MEK1/2 (U0126) and PI3K (wortmannin), and transfection with dominant negative mutants of p42/p44 mitogen-activated protein kinases (ERK2) or Akt. These results suggested that both p42/p44 MAPK and PI3K/Akt pathways participated in COX-2 expression induced by S1P in VSMCs. In accordance with these findings, S1P stimulated phosphorylation of p42/p44 MAPK and Akt, which was attenuated by U0126, LY294002, or wortmannin, respectively. Furthermore, this up-regulation of COX-2 mRNA and protein was blocked by a selective NF-κB inhibitor helenalin. Consistently, S1P-stimulated translocation of NF-κB into the nucleus was revealed by immnofluorescence staining. Moreover, S1P-stimulated activation of NF-κB promoter activity was blocked by phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and helenalin, but not by U0126, suggesting that involvement of PI3K/Akt in the activation of NF-κB. COX-2 promoter assay showed that S1P induced COX-2 promoter activity mediated through p42/p44 MAPK, PI3K/Akt, and NF-κB. These results suggested that in VSMCs, activation of p42/p44 MAPK, Akt and NF-κB pathways was essential for S1P-induced COX-2 gene expression. Understanding the mechanisms involved in S1P-induced COX-2 expression on VSMCs may provide potential therapeutic targets in the treatment of arteriosclerosis. J. Cell. Physiol. © 2006 Wiley-Liss, Inc.