Received for publication August 9, 2005.
Revised January 11, 2006.
Accepted for publication January 11, 2006.

PITAVASTATIN EFFECT ON ATP BINDING CASSETTE A1-MEDIATED LIPID EFFLUX FROM MACROPHAGES. Evidence for LXR-dependent and LXR-independent mechanisms of activation by cAMP

Abstract

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 (0.1-10µM) and compactin (10µM) 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 do 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 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.

Key words: ABCA1, LXR, cAMP, lipid efflux, macrophages, pitavastatin

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