Free cholesterol alters macrophage morphology and mobility by an ABCA1 dependent mechanism

被引:20
作者
Adorni, Maria Pia [1 ]
Favari, Elda [1 ]
Ronda, Nicoletta [1 ]
Granata, Agnese [2 ]
Bellosta, Stefano [2 ]
Arnaboldi, Lorenzo [2 ]
Corsini, Alberto [2 ]
Gatti, Rita [3 ]
Bernini, Franco [1 ]
机构
[1] Univ Parma, Dept Pharmacol & Biol Sci, I-43124 Parma, Italy
[2] Univ Milan, Dept Pharmacol Sci, I-20133 Milan, Italy
[3] Univ Parma, Dept Expt Med, Sect Histol, I-43125 Parma, Italy
关键词
Atherosclerosis; Macrophage; ABCA1; Membrane ruffling; Cell migration; Rac; CELLULAR CHOLESTEROL; PLASMA-MEMBRANE; DENSITY-LIPOPROTEIN; OXIDIZED LDL; MIGRATION; ATHEROSCLEROSIS; INHIBITION; TRANSPORT; GTPASES; CELLS;
D O I
10.1016/j.atherosclerosis.2010.12.004
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Objective: To investigate whether the morphological and functional changes typical of cell immobilization induced by free cholesterol (FC) accumulation in macrophages is related to the activity of the ATP-binding cassette transporter (ABCA1). Methods and results: FC loading induced actin rearrangement with ruffling and cell spreading in macrophages that normally express ABCA1, but to a significant lesser extent in ABCA1-KO mouse peritoneal macrophages (MPMs) and in normal cells upon pharmacological inhibition of ABCA1 with probucol. In ABCA1-KO MPMs and in probucol-treated J774 cell migration was inhibited to a lower extent by FC as compared to control cells. Similar results were found in stably ABCA1 knocked down J774 (ABCA1-KD-J774) obtained by RNA interference. FC accessible to cholesterol oxidase, a measure of plasma membrane FC content, was significantly higher in FC-loaded WT MPMs and control J774 than in FC-loaded ABCA1-KO MPMs, ABCA1-KD-J774 or probucol-treated J774. In parallel plasma membrane total phospholids and sphingomyelin increased after cholesterol loading in control J774 but not in ABCA1-KD-J774. In addition, apoA-I, that removes FC from ABCA1 specific pool, partially restored chemotactic response in FC-loaded control J774. No effect was observed with HDL2 that does not interact with ABCA1. Finally, FC-induced Rac activation was more efficient in control J774 than in ABCA1-KD-J774. and was prevented by probucol and apoA-I in control J774. Conclusion: In macrophages ABCA1 activity mediates FC ability to alter plasma membrane organization, to inhibit cell migration, and to activate a Rac-mediated signaling pathway. (C) 2010 Elsevier Ireland Ltd. All rights reserved.
引用
收藏
页码:70 / 76
页数:7
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