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Sphingosine-1-phosphate induces COX-2 expression via PI3K/Akt and p42/p44 MAPK pathways in rat vascular smooth muscle cells.
J Cell Physiol. 2006 Jun; 207(3):757-66.JC

Abstract

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-kappaB inhibitor helenalin. Consistently, S1P-stimulated translocation of NF-kappaB into the nucleus was revealed by immnofluorescence staining. Moreover, S1P-stimulated activation of NF-kappaB 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-kappaB. COX-2 promoter assay showed that S1P induced COX-2 promoter activity mediated through p42/p44 MAPK, PI3K/Akt, and NF-kappaB. These results suggested that in VSMCs, activation of p42/p44 MAPK, Akt and NF-kappaB 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.

Authors+Show Affiliations

Department of Physiology and Pharmacology, Chang Gung University, Tao-Yuan, Taiwan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16508949

Citation

Hsieh, Hsi-Lung, et al. "Sphingosine-1-phosphate Induces COX-2 Expression Via PI3K/Akt and P42/p44 MAPK Pathways in Rat Vascular Smooth Muscle Cells." Journal of Cellular Physiology, vol. 207, no. 3, 2006, pp. 757-66.
Hsieh HL, Wu CB, Sun CC, et al. Sphingosine-1-phosphate induces COX-2 expression via PI3K/Akt and p42/p44 MAPK pathways in rat vascular smooth muscle cells. J Cell Physiol. 2006;207(3):757-66.
Hsieh, H. L., Wu, C. B., Sun, C. C., Liao, C. H., Lau, Y. T., & 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. Journal of Cellular Physiology, 207(3), 757-66.
Hsieh HL, et al. Sphingosine-1-phosphate Induces COX-2 Expression Via PI3K/Akt and P42/p44 MAPK Pathways in Rat Vascular Smooth Muscle Cells. J Cell Physiol. 2006;207(3):757-66. PubMed PMID: 16508949.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sphingosine-1-phosphate induces COX-2 expression via PI3K/Akt and p42/p44 MAPK pathways in rat vascular smooth muscle cells. AU - Hsieh,Hsi-Lung, AU - Wu,Chou-Bing, AU - Sun,Chi-Chin, AU - Liao,Chang-Hui, AU - Lau,Ying-Tung, AU - Yang,Chuen-Mao, PY - 2006/3/2/pubmed PY - 2006/6/10/medline PY - 2006/3/2/entrez SP - 757 EP - 66 JF - Journal of cellular physiology JO - J. Cell. Physiol. VL - 207 IS - 3 N2 - 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-kappaB inhibitor helenalin. Consistently, S1P-stimulated translocation of NF-kappaB into the nucleus was revealed by immnofluorescence staining. Moreover, S1P-stimulated activation of NF-kappaB 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-kappaB. COX-2 promoter assay showed that S1P induced COX-2 promoter activity mediated through p42/p44 MAPK, PI3K/Akt, and NF-kappaB. These results suggested that in VSMCs, activation of p42/p44 MAPK, Akt and NF-kappaB 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. SN - 0021-9541 UR - https://www.unboundmedicine.com/medline/citation/16508949/Sphingosine_1_phosphate_induces_COX_2_expression_via_PI3K/Akt_and_p42/p44_MAPK_pathways_in_rat_vascular_smooth_muscle_cells_ L2 - https://doi.org/10.1002/jcp.20621 DB - PRIME DP - Unbound Medicine ER -