Oxidized low density lipoprotein activates peroxisome proliferator- activated receptor-α(PPARα) and PPARγ through MAPK-dependent COX-2 expression in macrophages

Abstract

It has been reported that oxidized low density lipoprotein (Ox-LDL) can activate both peroxisome proliferator-activated receptor-α(PPARα) and PPARγ. However, the detailed mechanisms of Ox-LDL-induced PPARα and PPARγ activation are not fully understood. In the present study, we investigated the effect of Ox-LDL on PPARα and PPARγ activation in macrophages. Ox-LDL, but not LDL, induced PPARα and PPARγ 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 PPARα and PPARγ activation. Ox-LDL induced phosphorylation of ERK1/2 and p38 MAPK, and ERK1/2 specific inhibition abrogated Ox-LDL-induced COX-2 expression and PPARα and PPARγ 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- Δ12,14-prostaglandin J2 (15d-PGJ2) level through ERK1/2-dependent overexpression of COX-2. Moreover, 15d-PGJ2 induced both PPARα and PPARγ 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 PPARα and PPARγ on Ox-LDL-induced mRNA expression of ATP-binding cassette transporter A1 and monocyte chemoattractant protein-1. Interestingly, specific inhibition of PPARα and PPARγ 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 PPARα and PPARγ activation in macrophages. These effects of Ox-LDL may control excess atherosclerotic progression. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.