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(Circulation Research. 2007;100:1394.)
© 2007 American Heart Association, Inc.

Editorials

Peroxisome Proliferator-Activated Receptors Mediate Pleiotropic Actions of Statins

Réjane Paumelle, Bart Staels

From the Institut Pasteur de Lille (R.P., B.S.), France; Inserm, U545 (R.P., B.S.), Lille, France; Université de Lille 2 (R.P., B.S.), France.

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

See related article, pages 1442–1451

Key Words: HMG-CoA reductase inhibitors • PPARs • atherosclerosis • macrophages • signalling pathways

An extract of the first 250 words of the full text is provided, because this article has no abstract.

High plasma concentrations of LDL-cholesterol (LDL-c) are a major risk factor for atherosclerosis, a chronic inflammatory disease of the large arteries. Statins are potent inhibitors of cholesterol biosynthesis which efficiently decrease plasma LDL-c concentrations. A large number of clinical trials has shown beneficial effects of statins in the primary and secondary prevention of cardiovascular disease. Although it is generally assumed that these beneficial effects are directly related to the decrease of LDL-c, certain benefits of statin therapy may occur earlier and possibly to a larger extent than what might be expected from changes in plasma LDL-c levels alone. These observations have led to the suggestion of effects beyond LDL-c-lowering, collectively termed "pleiotropic" effects.

Statins are competitive inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in cholesterol synthesis. As a result, intracellular cholesterol concentrations decrease after statin treatment leading to proteolytic activation of the transcription factor sterol responsive element-binding protein-2 (SREBP-2), which regulates several genes controlling cholesterol homeostasis, including the LDL-receptor (LDLR). Hence, as a consequence of increased LDL clearance, plasma LDL-c concentrations decrease.¹ The so-called pleiotropic effects of statins are though to be because of the inhibition of the parallel pathway of biosynthesis of isoprenoids, which constitute lipid attachments allowing membrane anchoring and activation of intracellular signaling molecules, such as the small GTP-binding proteins Rho, Ras, and Rac. These proteins then can activate various downstream signaling pathways including mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinases (ERKs) and p38-MAPKs, c-jun N-terminal kinases (JNKs) and phosphatidylinositol 3-kinase . . . [Full Text of this Article]

Related Article:

Statins Activate Peroxisome Proliferator-Activated Receptor Through Extracellular Signal-Regulated Kinase 1/2 and p38 Mitogen-Activated Protein Kinase–Dependent Cyclooxygenase-2 Expression in Macrophages

Miyuki Yano, Takeshi Matsumura, Takafumi Senokuchi, Norio Ishii, Yusuke Murata, Kayo Taketa, Hiroyuki Motoshima, Tetsuya Taguchi, Kazuhiro Sonoda, Daisuke Kukidome, Yoh Takuwa, Teruo Kawada, Michael Brownlee, Takeshi Nishikawa, and Eiichi Araki
Circ. Res. 2007 100: 1442-1451. [Abstract] [Full Text] [PDF]

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