Ezetimibe-mediated protection of vascular smooth muscle cells from cholesterol accumulation through the regulation of lipid metabolism-related gene expression.
BACKGROUND
Ezetimibe is a potent inhibitor of Niemann-Pick type C1-Like 1 and has been approved for the treatment of hypercholesterolemia. Our preliminary study showed that ezetimibe promotes cholesterol efﬂux from vascular smooth muscle cells (VSMCs). Our aim was to investigate the cellular mechanisms underlying the ezetimibe actions.


RESULTS
Rat VSMCs were converted to foam cells by incubation with cholesterol:methyl-β-cyclodextrin. The intracellular free cholesterol, total cholesterol, and the ratio of cholesteryl ester to total cholesterol were decreased after the incubation of VSMCs with different concentrations of ezetimibe (3, 10, 30, and 30 μmol/l) or treated with 30 μmol/l of ezetimibe for different time periods (6, 12, 24, and 48 h). Our results also showed that the expression of caveolin-1, liver X receptor α, and ATP-binding cassette transporter ABCA1 was enhanced, but the expression of nSREBP-1c was decreased in a concentration- and time-dependent manner. RNA interference was used to determine the roles of caveolin-1 and SREBP-1 in the lipid-lowering effect of ezetimibe. The results showed that caveolin-1 was involved in the regulation of intracellular cholesterol content, and the expression of caveolin-1 was repressed by SREBP-1.


CONCLUSIONS
The present study indicates that ezetimibe protects VSMCs from cholesterol accumulation by regulating the expression of lipid metabolism-related genes.
Department of Pharmacology, School of Pharmaceutical Sciences, Central South University, Changsha, PR China.
Yong-Zhen
YZ
Gong
Shao-Wei
SW
Sun
Hao-Yu
HY
Yuan
Xue-Jiao
XJ
Xie
Qin-Hui
QH
Tuo
Xue-Feng
XF
Yang
Xi
X
Tan
Xi-Long
XL
Zheng
Yan
Y
Xiong
Duan-Fang
DF
Liao
D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001384:Azetidines / Q000494:pharmacology*; D051242:Caveolin 1 / Q000235:genetics; D002784:Cholesterol / Q000494:pharmacology; D000069438:Ezetimibe; D005786:Gene Expression Regulation / Q000187:drug effects*; D050356:Lipid Metabolism / Q000187:drug effects* / Q000235:genetics; D000071518:Liver X Receptors; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D017207:Rats, Sprague-Dawley; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D047392:beta-Cyclodextrins / Q000494:pharmacology
D064286:ATP Binding Cassette Transporter 1; D000924:Anticholesteremic Agents; D001384:Azetidines; D051242:Caveolin 1; D002784:Cholesterol; D000069438:Ezetimibe; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D034741:RNA, Small Interfering; D051780:Sterol Regulatory Element Binding Protein 1; D047392:beta-Cyclodextrins; C577834:Abca1 protein, rat; C495537:Cav1 protein, rat; C000605215:Nr1h3 protein, rat; C497389:Srebf1 protein, rat; C108732:methyl-beta-cyclodextrin