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J. Biol. Chem., Vol. 279, Issue 13, 12300-12311, March 26, 2004

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Blood Lipid Mediator Sphingosine 1-Phosphate Potently Stimulates Platelet-derived Growth Factor-A and -B Chain Expression through S1P₁-G_i-Ras-MAPK-dependent Induction of Krüppel-like Factor 5^*

Soichiro Usui, Naotoshi Sugimoto, Noriko Takuwa, Satoru Sakagami, Shigeo Takata¶, Shuichi Kaneko, and Yoh Takuwa||

From the Departments of Molecular and Cellular Physiology, Internal Medicine, and ^¶Health Science, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa 920-8640, Japan

Platelet-derived growth factors (PDGFs), potent mitogens and chemoattractants for mesenchymal cell types, play essential roles in development of several organs including blood vessels, kidney, and lung, and are also implicated in the pathogenesis of atherosclerosis and malignancies. Blood lipid mediator sphingosine 1-phosphate (S1P) regulates migration, proliferation, and apoptosis in a variety of cell types through multiple G protein-coupled receptors of the Edg family, and is necessary for vascular formation at the developmental stage. We found in the present study that S1P induced severalfold increases in the mRNA and protein levels of PDGF-A and -B chains in vascular smooth muscle cells and neointimal cells. S1P stimulation of PDGF mRNA and protein expression was abolished by the small interfering RNA duplexes targeting S1P₁/Edg1 receptor subtype. S1P stimulated the small GTPase Ras in a G_i-dependent manner, and activated ERK and p38 MAPK in G_i- and Ras-dependent manners. Pertussis toxin pretreatment, adenovirus-mediated Asn¹⁷Ras expression, the MEK inhibitor PD98059, or the p38 MAPK inhibitor SB203580 markedly suppressed PDGF mRNA and protein up-regulation, indicating the involvement of G_i-Ras-ERK/p38 MAPK in S1P stimulation of PDGF expression. S1P stimulated expression of the transcription factor KLF5 in manners dependent on G_i, Ras, and ERK/p38 MAPK. Down-regulation of KLF5 by small interfering RNA duplexes abolished S1P-induced PDGF-A and -B chain expression. On the other hand, overexpression of KLF5 stimulated basal and S1P-induced PDGF expression. Either S1P stimulation or KLF5 overexpression increased the PDGF-B promoter activity in a cis-element-dependent manner. These results reveal the S1P₁-triggered, G_i-Ras-ERK/p38 MAPK-KLF5-dependent, stimulatory regulation of PDGF gene transcription in vascular smooth muscle cells.

Received for publication, May 13, 2003 , and in revised form, January 5, 2004.

^* This work was supported by grants from the Ministry of Education, Science, Sports and Culture of Japan, the Japan Society for the Promotion of Science, the Japan Society for the Promotion of Science Research for the Future Program, the Space Utilization Program by Japan Space Forum, and Hoh-Ansha Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Dept. of Physiology, Kanazawa University Graduate School of Medicine, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8640, Japan. Tel.: 81-76-265-2165; Fax: 81-76-234-4223; E-mail: ytakuwa{at}med.kanazawa-u.ac.jp.

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