Inhibition of Smooth Muscle Cell Proliferation by Ezetimibe via the Cyclin D1-MAPK Pathway

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  • Qin Li
    Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, China Institute of Pharmacy and Pharmacology, South China University, China
  • Yang Yun-Bo
    Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, Western University, Canada The Second Xiang-Ya Hospital, Central South University, China
  • Yang Yi-Xin
    Matthew Mailing Centre for Translational Transplantation Studies, London Health Sciences Centre, Western University, Canada
  • Gong Yong-Zhen
    Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, China
  • Li Xiao-Ling
    Cancer Research Institute, Central South University, China
  • Li Gui-Yuan
    Cancer Research Institute, Central South University, China
  • Luo Hong-Dan
    Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, China
  • Xie Xue-Jiao
    Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, China
  • Zheng Xi-Long
    Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, China Smooth Muscle Research Group, Department of Biochemistry & Molecular Biology, Libin Cardiovascular Institute of Alberta, Faculty of Medicine, University of Calgary, Canada
  • Liao Duan-Fang
    Division of Stem Cell Regulation and Application, School of Pharmacy, Hunan University of Chinese Medicine, China

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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.

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