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CARDIOVASCULAR

Pitavastatin Effect on ATP Binding Cassette A1-Mediated Lipid Efflux from Macrophages: Evidence for Liver X Receptor (LXR)-Dependent and LXR-Independent Mechanisms of Activation by cAMP

Department of Pharmacological and Biological Sciences and Applied Chemistries, University of Parma, Parma, Italy (I.Z., F.P., E.F., F.B.); and Department of Biosciences, Karolinska Institutet Novum, Huddinge, Sweden (K.R.S., J.-Å.G.)

The promotion of lipid efflux from macrophages is an important ATP binding cassette A1 (ABCA1)-mediated antiatherosclerotic mechanism that prevents peripheral tissues from foam cell accumulation. Statins exert beneficial antiatherosclerotic effects on cardiovascular disease correlated to the cholesterol-lowering properties and the pleiotropic activities. In this work, we investigated the ability of statins to modulate ABCA1-mediated lipid efflux from macrophages, where the protein expression was differently induced. Pitavastatin (0.1–10 µM) and compactin (10 µM) reduced both cholesterol and phospholipid efflux up to 60% from macrophages expressing ABCA1 upon treatment with 8-(4-chlorophenylthio)-cyclic AMP (cpt-cAMP), and this was secondary to a reduction of ABCA1 mRNA and protein content. Conversely, statins did not affect ABCA1 activity when the protein was up-regulated by 22-hydroxycholesterol/9-cis-retinoic acid or through cholesterol loading. Statin inhibition of lipid efflux induced by cpt-cAMP was reversed in the presence of mevalonate, 22-hydroxycholesterol, and cholesterol but not geranyl geraniol. In macrophages obtained from liver X receptor (LXR)-deficient mice, cpt-cAMP still promoted cholesterol efflux, but pitavastatin did not exert any effect. The present work shows that statins may inhibit ABCA1-mediated lipid efflux in macrophages only when ABCA1 protein expression is induced by cpt-cAMP and provides evidence that cAMP may activate ABCA1 independently of an increase of intracellular sterol synthesis but through at least two pathways: one independent of LXR and one involving an intracellular sterol(s) acting as LXR ligand(s). In addition, the lack of inhibitory effect on lipid efflux in cholesterol-loaded macrophages is likely to exclude a potential negative pleiotropic effect by statins.

Address correspondence to: Prof. Franco Bernini, Department of Pharmacological and Biological Sciences and Applied Chemistries, School of Pharmacy, University of Parma, viale delle Scienze 27/A, 43100 Parma, Italy. E-mail: fbernini{at}unipr.it

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