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

Abstract

Abstract-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 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 PPAR␥ activation. Statins also activate PPAR␣ via COX-2-dependent increases in 15d-PGJ 2 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-PGJ 2 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. (Circ Res. 2007;100:1442-1451.) Key Words: cyclooxygenase Ⅲ MAPK Ⅲ macrophages Ⅲ PPAR Ⅲ statins 3 -Hydroxyl-3-methylglutaryl coenzyme A reductase inhibitors (statins) are known to reduce the incidence of cardiovascular events and death, and these benefits are mainly caused by their lipid-lowering effects. 1 However, recent evidence has suggested that the beneficial effects by statins are independent of their cholesterol-lowering effects. 2 Cholesterol is synthesized via the isoprenoid biosynthetic pathway. 3 In this pathway, isopentenyl-PP is the basic isoprene unit used for synthesis of all subsequent isoprenoids. 3 Among the isoprenoids, farnesylpyrophosphate (FPP) and geranylgeranylpyrophosphate (GGPP) serve as important lipid attachments for several proteins, including the small GTP-binding protein Ras and Ras-like proteins, such as Rho, Rac, and Cdc42, whose proper membrane localization and function are dependent on isoprenylation. 3 The pleio...

Inhibition of Intestinal Polyp Formation by Pitavastatin, a HMG-CoA Reductase Inhibitor

“…Statins are reported to suppress some inflammatory adipocytokines through the PPARg activation (32). Thus, we further evaluated the effect of pitavastatin on PPARg activation in nonpolyp parts of the small intestine and liver of Min mice.…”

The role of the amino-terminal domain in the interaction of unliganded peroxisome proliferator-activated receptor γ-2 with nuclear receptor co-repressor

“…It is currently difficult to completely eliminate the endogenous ligands produced by cells (DiRenzo et al 1997, Werman et al 1997, Kim et al 1998, Camp et al 2001, Madsen et al 2003, Tzameli et al 2004, Yano et al 2007. The existence of endogenous ligands may mask the silencing by unliganded PPARG2.…”

“…To detect the silencing effect of wild-type PPARG2 in a conventional reporter assay, it is necessary to maintain the majority of PPARG2 molecules in truly an unliganded condition. Endogenous ligands for PPARG2 are reported to be generated by 3T3-L1 preadipocytes (Kim et al 1998, Camp et al 2001, Madsen et al 2003, Tzameli et al 2004) and macrophages (Yano et al 2007). Similar substances may also be generated by CV1 cells (DiRenzo et al 1997, Werman et al 1997, which have been often used in the studies of NHRs.…”

The Pleiotropic Effects of Statins in the Prevention of Atherosclerosis

“…Statins are reported to activate PPAR-γ and inhibit LPS-induced cytokine expression in macrophages [21]. These findings are supported by data demonstrating that statins stabilize atherosclerotic plaques through the activation of PPAR-γ and that combined administration of simvastatin with PPAR-γ agonists elicits additive effects on atherosclerotic plaque regression [22][23][24].…”