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.