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.[1]References
- Pitavastatin-induced downregulation of CCR2 and CCR5 in monocytes is associated with the arrest of cell-cycle in S phase. Fujino, M., Miura, S., Matsuo, Y., Tanigawa, H., Kawamura, A., Saku, K. Atherosclerosis (2006) [Pubmed]
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