TY - JOUR
T1 - 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
AU - Yano, Miyuki
AU - Matsumura, Takeshi
AU - Senokuchi, Takafumi
AU - Ishii, Norio
AU - Murata, Yusuke
AU - Taketa, Kayo
AU - Motoshima, Hiroyuki
AU - Taguchi, Tetsuya
AU - Sonoda, Kazuhiro
AU - Kukidome, Daisuke
AU - Takuwa, Yoh
AU - Kawada, Teruo
AU - Brownlee, Michael
AU - Nishikawa, Takeshi
AU - Araki, Eiichi
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2007/5
Y1 - 2007/5
N2 - 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.
AB - 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.
KW - Cyclooxygenase
KW - MAPK
KW - Macrophages
KW - PPAR
KW - Statins
UR - http://www.scopus.com/inward/record.url?scp=34249723258&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34249723258&partnerID=8YFLogxK
U2 - 10.1161/01.RES.0000268411.49545.9c
DO - 10.1161/01.RES.0000268411.49545.9c
M3 - Article
C2 - 17463321
AN - SCOPUS:34249723258
SN - 0009-7330
VL - 100
SP - 1442
EP - 1451
JO - Circulation research
JF - Circulation research
IS - 10
ER -