Pitavastatin-induced downregulation of CCR2 and CCR5 in monocytes is associated with the arrest of cell-cycle in S phase.
The pleiotropic effects of statin, including its anti-inflammatory effects, via chemokines may be independent of statin-induced cholesterol reduction. Therefore, we examined the effect of pitavastatin on cell proliferation and the association between chemokine receptors (CCR2 and CCR5) and their ligands, RANTES (regulated upon activation, normal T cell-expressed and secreted) and monocyte chemotactic protein-1 (MCP-1), in monocytes. Pitavastatin but not pravastatin inhibited cell proliferation in a dose-dependent manner and showed S-phase arrest associated with the downregulation of CCR2 and CCR5 expression in human monocytic tumor cells (U937 cells). Although the anti-proliferative effects of pitavastatin were not inhibited by lower concentrations of RANTES and MCP-1, overexpression of CCR2/CCR5 significantly blocked the anti-proliferation with a low concentration of RANTES or MCP-1. Pitavastatin upregulated p21(waf1) but not p27(kip1), and did not change the expression levels of cyclin D1 or cdk4. In addition, RANTES and MCP-1 upregulated cyclin D1 in the presence of pitavastatin. In conclusion, the anti-proliferative effect of pitavastatin, but not pravastatin, through the downregulation of CCR2/CCR5 may be a pleiotropic effect. This effect may be anti-atherogenic in monocytes.
Fujino
Masahiro
M
Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-Ku, Fukuoka, 814-0180, Japan.
Miura
Shin-ichiro
S
Matsuo
Yoshino
Y
Tanigawa
Hiroaki
H
Kawamura
Akira
A
Saku
Keijiro
K
D000924:Anticholesteremic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D018932:Chemokine CCL2 / Q000378:metabolism / Q000494:pharmacology; D018946:Chemokine CCL5 / Q000378:metabolism / Q000494:pharmacology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism*; D016196:S Phase / Q000187:drug effects / Q000276:immunology; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D000924:Anticholesteremic Agents; C111835:CCL2 protein, human; C515334:CCR2 protein, human; C493956:CDKN1A protein, human; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D011804:Quinolines; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D017035:Pravastatin; C108475:pitavastatin