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.
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 microM) and compactin (10 microM) 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.
Zanotti
Ilaria
I
Department of Pharmacological and Biological Sciences and Applied Chemistries, School of Pharmacy, University of Parma, Italy.
Potì
Francesco
F
Favari
Elda
E
Steffensen
Knut R
KR
Gustafsson
Jan-Ake
JA
Bernini
Franco
F
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis*; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects*; D000071518:Liver X Receptors; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D057093:Orphan Nuclear Receptors; D010743:Phospholipids / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010743:Phospholipids; D011804:Quinolines; D018160:Receptors, Cytoplasmic and Nuclear; D002784:Cholesterol; D000242:Cyclic AMP; C108475:pitavastatin