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(Circulation Research. 2007;100:1442.)
© 2007 American Heart Association, Inc.

Molecular Medicine

Statins Activate Peroxisome Proliferator-Activated Receptor Through Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase–Dependent Cyclooxygenase-2 Expression in Macrophages

Miyuki Yano^*, Takeshi Matsumura^*, Takafumi Senokuchi, Norio Ishii, Yusuke Murata, Kayo Taketa, Hiroyuki Motoshima, Tetsuya Taguchi, Kazuhiro Sonoda, Daisuke Kukidome, Yoh Takuwa, Teruo Kawada, Michael Brownlee, Takeshi Nishikawa, Eiichi Araki

From the Department of Metabolic Medicine (M.Y., T.M., T.S., N.I., Y.M., K.T., H.M., T.T., K.S., D.K., T.N., E.A.), Graduate School of Medical Sciences, Kumamoto University, Japan; Department of Physiology (Y.T.), Graduate School of Medicine, Kanazawa University, Japan; Laboratory of Nutrition Chemistry (T.K.), Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Japan; and Department of Medicine, Diabetes Research Center (M.B.), Albert Einstein College of Medicine, Bronx, NY.

Correspondence to Takeshi Matsumura, MD, PhD, Department of Metabolic Medicine, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto 860-8556, Japan. E-mail takeshim{at}gpo.kumamoto-u.ac.jp

Both statins and peroxisome proliferator-activated receptor (PPAR) ligands have been reported to protect against the progression of atherosclerosis. In the present study, we investigated the effects of statins on PPAR activation in macrophages. Statins increased PPAR activity, which was inhibited by mevalonate, farnesylpyrophosphate, or geranylgeranylpyrophosphate. Furthermore, a farnesyl transferase inhibitor and a geranylgeranyl transferase inhibitor mimicked the effects of statins. Statins inhibited the membrane translocations of Ras, RhoA, Rac, and Cdc42, and overexpression of dominant-negative mutants of RhoA (DN-RhoA) and Cdc42 (DN-Cdc42), but not of Ras or Rac, increased PPAR activity. Statins induced extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) activation. However, DN-RhoA and DN-Cdc42 activated p38 MAPK, but not ERK1/2. ERK1/2- or p38 MAPK–specific inhibitors abrogated statin-induced PPAR activation. Statins induced cyclooxygenase (COX)-2 expression and increased intracellular 15-deoxy-^12,14-prostaglandin J₂ (15d-PGJ₂) levels through ERK1/2- and p38 MAPK–dependent pathways, and inhibitors or small interfering RNA of COX-2 inhibited statin-induced PPAR activation. Statins also activate PPAR via COX-2–dependent increases in 15d-PGJ₂ levels. We further demonstrated that statins inhibited lipopolysaccharide-induced tumor necrosis factor or monocyte chemoattractant protein-1 mRNA expression, and these effects by statins were abrogated by the PPAR antagonist T0070907 or by small interfering RNA of PPAR or PPAR. Statins also induced ATP-binding cassette protein A1 or CD36 mRNA expression, and these effects were suppressed by small interfering RNAs of PPAR or PPAR. In conclusion, statins induce COX-2–dependent increase in 15d-PGJ₂ level through a RhoA- and Cdc42-dependent p38 MAPK pathway and a RhoA- and Cdc42-independent ERK1/2 pathway, thereby activating PPAR. Statins also activate PPAR via COX-2–dependent pathway. These effects of statins may explain their antiatherogenic actions.

Key Words: cyclooxygenase • MAPK • macrophages • PPAR • statins

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