title: Inhibition of smooth muscle cell proliferation by ezetimibe via the cyclin D1-MAPK pathway.
abstract: Proliferation of vascular smooth muscle cells (VSMCs) contributes to the development of atherosclerosis. Ezetimibe is a new lipid lowering agent that inhibits cholesterol absorption. In the present study we attempted to investigate whether ezetimibe has any effect on VSMC proliferation and the potential mechanisms involved. Our data showed ezetimibe abrogated the proliferation and migration of primary rat VSMCs induced by Chol:MβCD. Mechanically, we found that ezetimibe was capable of abolishing cyclin D1, CDK2, phospho-Rb (p-Rb), and E2F protein expressions that were upregulated by Chol:MβCD treatment. In addition, Ezetimibe was able to reverse cell cycle progression induced by Chol:MβCD, which was further supported by its down-regulation of cyclin D1 promoter activity in the presence of Chol:MβCD. Furthermore, ezetimibe abrogated the increment of phospho-ERK1/2 (p-ERK1/2) and nuclear accumulation of ERK1/2 in VSMCs induced by Chol:MβCD. Inhibition of the MAPK pathway by using ERK1/2 inhibitor PD98059 attenuated the reduction effect of ezetimibe on the expressions of phosphor-MEK1 (p-MEK1), p-ERK1/2, and cyclin D1. Taken together our data suggest that ezetimibe inhibits Chol:MβCD-induced VSMCs proliferation and leads to cell cycle arrest at the G0/G1 phase by suppressing cyclin D1 expression via the MAPK signaling pathway. These novel findings support the potential pleiotropic effect of ezetimibe in cardiovascular disease.
authors.affiliation: Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, China.
authors.forename: Li
authors.initials: L
authors.lastname: Qin
authors.forename: Yun-Bo
authors.initials: YB
authors.lastname: Yang
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Yang
authors.forename: Yong-Zhen
authors.initials: YZ
authors.lastname: Gong
authors.forename: Xiao-Ling
authors.initials: XL
authors.lastname: Li
authors.forename: Gui-Yuan
authors.initials: GY
authors.lastname: Li
authors.forename: Hong-Dan
authors.initials: HD
authors.lastname: Luo
authors.forename: Xue-Jiao
authors.initials: XJ
authors.lastname: Xie
authors.forename: Xi-Long
authors.initials: XL
authors.lastname: Zheng
authors.forename: Duan-Fang
authors.initials: DF
authors.lastname: Liao
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001384:Azetidines / Q000494:pharmacology* / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000235:genetics; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000378:metabolism*; D003864:Depression, Chemical; D000069438:Ezetimibe; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D058990:Molecular Targeted Therapy; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; C530106:Ccnd1 protein, rat; D019938:Cyclin D1; D000069438:Ezetimibe