Statins activate peroxisome proliferator-activated receptor γ 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

Research output: Contribution to journalArticlepeer-review

170 Scopus citations

Abstract

Both statins and peroxisome proliferator-activated receptor (PPAR)γ ligands have been reported to protect against the progression of atherosclerosis. In the present study, we investigated the effects of statins on PPARγ activation in macrophages. Statins increased PPARγ 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 PPARγ 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 PPARγ activation. Statins induced cyclooxygenase (COX)-2 expression and increased intracellular 15-deoxy-Δ-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 PPARγ activation. Statins also activate PPARα via COX-2-dependent increases in 15d-PGJ2 levels. We further demonstrated that statins inhibited lipopolysaccharide-induced tumor necrosis factor α or monocyte chemoattractant protein-1 mRNA expression, and these effects by statins were abrogated by the PPARγ antagonist T0070907 or by small interfering RNA of PPARγ or PPARα. Statins also induced ATP-binding cassette protein A1 or CD36 mRNA expression, and these effects were suppressed by small interfering RNAs of PPARγ or PPARα. 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 PPARγ. Statins also activate PPARα via COX-2-dependent pathway. These effects of statins may explain their antiatherogenic actions.

Original languageEnglish (US)
Pages (from-to)1442-1451
Number of pages10
JournalCirculation research
Volume100
Issue number10
DOIs
StatePublished - May 2007

Keywords

  • Cyclooxygenase
  • MAPK
  • Macrophages
  • PPAR
  • Statins

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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