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J. Biol. Chem., Vol. 283, Issue 15, 9852-9862, April 11, 2008

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Oxidized Low Density Lipoprotein Activates Peroxisome Proliferator-activated Receptor- (PPAR) and PPAR through MAPK-dependent COX-2 Expression in Macrophages^*

Kayo Taketa, Takeshi Matsumura¹, Miyuki Yano, Norio Ishii, Takafumi Senokuchi, Hiroyuki Motoshima, Yusuke Murata, Shokei Kim-Mitsuyama, Teruo Kawada^¶, Hiroyuki Itabe^||, Motohiro Takeya^**, Takeshi Nishikawa, Kaku Tsuruzoe, and Eiichi Araki

From the Department of Metabolic Medicine, Department of Pharmacology and Molecular Therapeutics, and ^**Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 861-8556, the ^¶Laboratory of Nutrition Chemistry, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Gokasyou, Uji, Kyoto 611-0011, and the ^||Department of Biological Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan

It has been reported that oxidized low density lipoprotein (Ox-LDL) can activate both peroxisome proliferator-activated receptor- (PPAR) and PPAR. However, the detailed mechanisms of Ox-LDL-induced PPAR and PPAR activation are not fully understood. In the present study, we investigated the effect of Ox-LDL on PPAR and PPAR activation in macrophages. Ox-LDL, but not LDL, induced PPAR and PPAR activation in a dose-dependent manner. Ox-LDL transiently induced cyclooxygenase-2 (COX-2) mRNA and protein expression, and COX-2 specific inhibition by NS-398 or meloxicam or small interference RNA of COX-2 suppressed Ox-LDL-induced PPAR and PPAR activation. Ox-LDL induced phosphorylation of ERK1/2 and p38 MAPK, and ERK1/2 specific inhibition abrogated Ox-LDL-induced COX-2 expression and PPAR and PPAR activation, whereas p38 MAPK-specific inhibition had no effect. Ox-LDL decreased the amounts of intracellular long chain fatty acids, such as arachidonic, linoleic, oleic, and docosahexaenoic acids. On the other hand, Ox-LDL increased intracellular 15-deoxy-^12,14-prostaglandin J₂ (15d-PGJ₂) level through ERK1/2-dependent overexpression of COX-2. Moreover, 15d-PGJ₂ induced both PPAR and PPAR activation. Furthermore, COX-2 and 15d-PGJ₂ expression and PPAR activity were increased in atherosclerotic lesions of apoE-deficient mice. Finally, we investigated the involvement of PPAR and PPAR on Ox-LDL-induced mRNA expression of ATP-binding cassette transporter A1 and monocyte chemoattractant protein-1. Interestingly, specific inhibition of PPAR and PPAR suppressed Ox-LDL-induced ATP-binding cassette transporter A1 mRNA expression and enhanced Ox-LDL-induced monocyte chemoattractant protein-1 mRNA expression. In conclusion, Ox-LDL-induced increase in 15d-PGJ₂ level through ERK1/2-dependent COX-2 expression is one of the mechanisms of PPAR and PPAR activation in macrophages. These effects of Ox-LDL may control excess atherosclerotic progression.

Received for publication, April 20, 2007 , and in revised form, December 26, 2007.

^* This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, Japan (Grant 20398192 to T. M.), by a grant from the Takeda Science Foundation (to T. M.), and by a grant from the Japan Diabetes Foundation (to T. M.). 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 To whom correspondence should be addressed. Tel.: 81-96-373-5169; Fax: 81-96-366-8397; E-mail: takeshim{at}gpo.kumamoto-u.ac.jp.

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