Statins activate peroxisome proliferator-activated receptor gamma through extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase-dependent cyclooxygenase-2 expression in macrophages.
Both statins and peroxisome proliferator-activated receptor (PPAR)gamma ligands have been reported to protect against the progression of atherosclerosis. In the present study, we investigated the effects of statins on PPARgamma activation in macrophages. Statins increased PPARgamma 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 PPARgamma 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 PPARgamma activation. Statins induced cyclooxygenase (COX)-2 expression and increased intracellular 15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) levels through ERK1/2- and p38 MAPK-dependent pathways, and inhibitors or small interfering RNA of COX-2 inhibited statin-induced PPARgamma activation. Statins also activate PPARalpha via COX-2-dependent increases in 15d-PGJ(2) levels. We further demonstrated that statins inhibited lipopolysaccharide-induced tumor necrosis factor alpha or monocyte chemoattractant protein-1 mRNA expression, and these effects by statins were abrogated by the PPARgamma antagonist T0070907 or by small interfering RNA of PPARgamma or PPARalpha. Statins also induced ATP-binding cassette protein A1 or CD36 mRNA expression, and these effects were suppressed by small interfering RNAs of PPARgamma or PPARalpha. In conclusion, statins induce COX-2-dependent increase in 15d-PGJ(2) level through a RhoA- and Cdc42-dependent p38 MAPK pathway and a RhoA- and Cdc42-independent ERK1/2 pathway, thereby activating PPARgamma. Statins also activate PPARalpha via COX-2-dependent pathway. These effects of statins may explain their antiatherogenic actions.
Yano
Miyuki
M
Department of Metabolic Medicine, Graduate School of Medical Sciences, Kumamoto University, Honjo, Kumamoto, Japan.
Matsumura
Takeshi
T
Senokuchi
Takafumi
T
Ishii
Norio
N
Murata
Yusuke
Y
Taketa
Kayo
K
Motoshima
Hiroyuki
H
Taguchi
Tetsuya
T
Sonoda
Kazuhiro
K
Kukidome
Daisuke
D
Takuwa
Yoh
Y
Kawada
Teruo
T
Brownlee
Michael
M
Nishikawa
Takeshi
T
Araki
Eiichi
E
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005227:Fatty Acids / Q000032:analysis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007249:Inflammation / Q000517:prevention & control; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D047493:PPAR alpha / Q000187:drug effects; D047495:PPAR gamma / Q000187:drug effects* / Q000502:physiology; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000032:analysis; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
C477819:15-deoxyprostaglandin J2; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D018955:CD36 Antigens; D005227:Fatty Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008070:Lipopolysaccharides; D047493:PPAR alpha; D047495:PPAR gamma; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein; D015230:Prostaglandin D2