[Effect of pitavastatin on macrophage cholesterol metabolism].
OBJECTIVE
Pitavastatin is the first totally synthetic HMG-Co A reductase inhibitor in Japan that significantly reduces LDL cholesterol while raising HDL cholesterol. Clinical trial showed that pitavastatin has potent effects for LDL cholesterol lowering and is expected effectively to prevent atherosclerosis. To clarify the mechanism of reduction of atherosclerosis by pitavastatin, we examined the effect of pitavastatin on foam cell formation of RAW264.7 macrophages.


RESULTS
Macrophages were cultured with pitavastatin for 24 h and exposed to oxidized LDL with pitavastatin for 3 days. Pitavastatin decreased the cellular cholesteryl ester content in a dose-dependent manner, and this effect was not via inhibition of HMG-CoA reductase because the 3-30 nM pitavastatin did not inhibit [14C]cholesterol synthesis from [14C]acetic acid and the effect was not influenced by addition of mevalonic acid. Pitavastatin increased neutral cholesterol esterase (NCEase) activity and did not affect ACAT activity, and decreased the expression of CD36 and ABCA1 mRNA. The mechanism of the increase of NCEase activity was that pitavastatin directly modified the substrate state, which was cholesterol oleate emulsified with lecithin.


CONCLUSIONS
Clinical blood concentrations of pitavastatin prevent foam cell formation of RAW macrophages by oxidized LDL, and this was not via inhibition of HMG-CoA reductase, and modify substrate condition.
Akisato
Yoshie
Y
Department of Clinical Pharmacology, Graduate School of Chiba University, Chiba University Hospital, Japan.
Ishii
Itsuko
I
Kitahara
Masaki
M
Tamaki
Taro
T
Saito
Yasushi
Y
Kitada
Mitsukazu
M
D000818:Animals; D002478:Cells, Cultured; D008076:Cholesterol, HDL / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000378:metabolism*; D005487:Foam Cells / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051379:Mice; D011804:Quinolines / Q000494:pharmacology*; D002787:Sterol Esterase / Q000378:metabolism
D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; D002787:Sterol Esterase; C108475:pitavastatin