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(Circulation Research. 2006;98:361.)
© 2006 American Heart Association, Inc.

Molecular Medicine

Acute Antiinflammatory Properties of Statins Involve Peroxisome Proliferator–Activated Receptor- via Inhibition of the Protein Kinase C Signaling Pathway

Réjane Paumelle, Christophe Blanquart, Olivier Briand, Olivier Barbier, Christian Duhem, Gaëtane Woerly, Frédéric Percevault, Jean-Charles Fruchart, David Dombrowicz, Corine Glineur, Bart Staels

From the Institut Pasteur de Lille (R.P., C.B., O. Briand, O. Barbier, C.D., F.P., J.-C.F., C.G., B.S.), Département d’Athérosclérose; INSERM, U545 (R.P., C.B., O. Briand, O. Barbier, C.D., F.P., J.-C.F., C.G., B.S.); Université de Lille 2 (R.P., C.B., O. Briand, O. Barbier, C.D., F.P., J.-C.F., C.G., B.S.); and INSERM, U547 (G.W., D.D.), Institut Pasteur de Lille, Lille, France.

Correspondence to Bart Staels, INSERM U545, Institut Pasteur de Lille, 1 rue Calmette, BP 245, 59019 Lille, France. E-mail Bart.Staels{at}pasteur-lille.fr

Statins are inhibitors of 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase used in the prevention of cardiovascular disease (CVD). In addition to their cholesterol-lowering activities, statins exert pleiotropic antiinflammatory effects, which might contribute to their beneficial effects not only on CVD but also on lipid-unrelated immune and inflammatory diseases, such as rheumatoid arthritis, asthma, stroke, and transplant rejection. However, the molecular mechanisms involved in these antiinflammatory properties of statins are unresolved. Here we show that the peroxisome proliferator–activated receptor (PPAR) mediates antiinflammatory effects of simvastatin in vivo in models of acute inflammation. The inhibitory effects of statins on lipopolysaccharide-induced inflammatory response genes were abolished in PPAR-deficient macrophages and neutrophils. Moreover, simvastatin inhibited PPAR phosphorylation by lipopolysaccharide-activated protein kinase C (PKC) . A constitutive active form of PKC inhibited nuclear factor B transrepression by PPAR whereas simvastatin enhanced transrepression activity of wild-type PPAR, but not of PPAR mutated in its PKC phosphorylation sites. These data indicate that the acute antiinflammatory effect of simvastatin occurs via PPAR by a mechanism involving inhibition of PKC inactivation of PPAR transrepression activity.

Key Words: inflammation • macrophages • neutrophils • nuclear receptors • statins • PKC

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