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Induction of Scavenger Receptor Class B Type I Is Critical for Simvastatin Enhancement of High-Density Lipoprotein-Induced Anti-Inflammatory Actions in Endothelial Cells¹

Takao Kimura^2,*,, Chihiro Mogi^2,*, Hideaki Tomura^*, Atsushi Kuwabara^*,, Doon-Soon Im, Koichi Sato^*, Hitoshi Kurose, Masami Murakami and Fumikazu Okajima^3,*

^* Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, and Department of Clinical Laboratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan; Laboratory of Pharmacology, College of Pharmacy, Pusan National University, Busan, Republic of Korea; and Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan

Changes in plasma lipoprotein profiles, especially low levels of high-density lipoprotein (HDL), are a common biomarker for several inflammatory and immune diseases, including atherosclerosis and rheumatoid arthritis. We examined the effect of simvastatin on HDL-induced anti-inflammatory actions. HDL and sphingosine 1-phosphate (S1P), a bioactive lipid component of the lipoprotein, inhibited TNF -induced expression of VCAM-1, which was associated with NO synthase (NOS) activation, in human umbilical venous endothelial cells. The HDL- but not S1P-induced anti-inflammatory actions were enhanced by a prior treatment of the cells with simvastatin in a manner sensitive to mevalonic acid. Simvastatin stimulated the expression of scavenger receptor class B type I (SR-BI) and endothelial NOS. As for S1P receptors, however, the statin inhibited the expression of S1P₃ receptor mRNA but caused no detectable change in S1P₁ receptor expression. The reconstituted HDL, a stimulator of SR-BI, mimicked HDL actions in a simvastatin-sensitive manner. The HDL- and reconstituted HDL-induced actions were blocked by small interfering RNA specific to SR-BI regardless of simvastatin treatment. The statin-induced expression of SR-BI was attenuated by constitutively active RhoA and small interfering RNA specific to peroxisome proliferator-activated receptor-. Administration of simvastatin in vivo stimulated endothelial SR-BI expression, which was accompanied by the inhibition of the ex vivo monocyte adhesion in aortas from TNF -injected mice. In conclusion, simvastatin induces endothelial SR-BI expression through a RhoA- and peroxisome proliferator-activated receptor--dependent mechanism, thereby enhancing the HDL-induced activation of NOS and the inhibition of adhesion molecule expression.

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.

¹ This work was supported by a Grant-in-Aid for scientific research from the Japan Society for the Promotion of Science (to T.K., F.O., H.T., K.S., and A.K.); a grant of the 21^st Century Center of Excellence Program (to T.K.) and Global Center of Excellence Program (to K.S. and C.M.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; grants from Yamanouchi Foundation for Research on Metabolic Disorders (to F.O.), Uehara Memorial Foundation (to F.O.), and Takeda Science Foundation (to F.O., H.T., and K.S.); and a Grand-in-Aid for 2007 Korea-Japan Joint Research Project from Korea Science and Engineering Foundation (to D.-S.I. and F.O.).

² T.K. and C.M. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Fumikazu Okajima, Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi 371-8512, Japan. E-mail address: fokajima{at}showa.gunma-u.ac.jp

⁴ Abbreviations used in this paper: LDL, low-density lipoprotein; HDL, high-density lipoprotein; rHDL, reconstituted HDL; apoA-I, apolipoprotein A-I; eNOS, endothelial NO synthase; SR-BI, scavenger receptor class B type I; L-NAME, L-N^G-nitroarginine methyl ester hydrochloride; siRNA, small interfering RNA; HUVEC, human umbilical vein endothelial cell; PPAR-, peroxisome proliferator-activated receptor-.

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