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: Li Qin, Yun-Bo Yang, Yi-Xin Yang, Yong-Zhen Gong, Xiao-Ling Li, Gui-Yuan Li, Hong-Dan Luo, Xue-Jiao Xie, Xi-Long Zheng, Duan-Fang Liao
• Journal: Journal of pharmacological sciences (J Pharmacol Sci) Vol. 125 Issue 3 Pg. 283-91 ( 2014) ISSN: 1347-8648 [Electronic] Japan
• PMID: 25048018 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticholesteremic Agents
• Azetidines
• Ccnd1 protein, rat
• Cyclin D1
• Ezetimibe

Topics

• Animals
• Anticholesteremic Agents (pharmacology, therapeutic use)
• Azetidines (pharmacology, therapeutic use)
• Cardiovascular Diseases (drug therapy, genetics)
• Cell Cycle Checkpoints (drug effects, genetics)
• Cell Movement (drug effects)
• Cell Proliferation (drug effects, genetics)
• Cells, Cultured
• Cyclin D1 (metabolism)
• Depression, Chemical
• Ezetimibe
• MAP Kinase Signaling System (drug effects)
• Male
• Molecular Targeted Therapy
• Muscle, Smooth, Vascular (cytology)
• Rats, Sprague-Dawley
• Up-Regulation (drug effects)