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Front. Pharmacol. | doi: 10.3389/fphar.2019.00485

All-Trans-Retinoic Acid suppresses neointimal hyperplasia and inhibits vascular smooth muscle cell proliferation via activation of AMPK signaling Pathway

Jingzhi Zhang1,  Bo Deng1, XIaoli Jiang1, Ningning Liu1, Shuangwei Zhang1, Min Cai1, Yongzhen Tan1, Guiqiong Huang1, Wen Jin1,  Bin Liu1* and Shiming Liu1
  • 1Guangzhou Medical University, China

The proliferation of vascular smooth muscle cell (VSMC) is extensively involved in pathogenesis of neointimal hyperplasia. All-Trans-Retinoic Acid (ATRA) is a natural metabolite of vitamin A. Here, we investigated the involvement of AMP-activated protein kinase (AMPK) in the anti-neointimal hyperplasia actions of ATRA. In this study, we found treatment with ATRA significantly reduced neointimal hyperplasia in left common carotid artery ligation mice model. Accordingly, we found that ATRA reduced the cell proliferation of A7r5, a rat VSMC cell line in a dose- and time-dependent manner. Our results also demonstrated that ATRA altered the expression of proliferation-related proteins, including CyclinD1, CyclinD3 and CDK4 in A7r5 cells. ATRA dose-dependently enhanced the phosphorylation level of AMPKα (Thr172) in the left common carotid artery of model mice. Also, the phosphorylation level of AMPKα in A7r5 was significantly increased in a dose- and time-independent manner. In addition, ATRA dose-dependently reduced the phosphorylation levels of mTOR and mTOR target proteins p70 S6 kinase (p70S6K) and 4E-binding protein 1 (4EBP1). Notably, inhibition of AMPKα by AMPK inhibitor (Compound C) negated the protective effect of ATRA on VSMC proliferation. Molecular docking showed that ATRA could dock into agonist binding site of AMPK, and the binding energy between AMPK and ATRA was -7.91 kcal/mol. Molecular dynamics simulations showed that the binding of AMPK-ATRA was stable. These data demonstrated that ATRA might inhibit neointimal hyperplasia and VSMC proliferation by direct activation of AMPK and inhibition of mTOR signaling.

Keywords: all-trans-retinoic acid, Neointimal Hyperplasia, vascular smooth muscle cell, proliferation, AMP-activated protein kinase

Received: 30 Oct 2018; Accepted: 17 Apr 2019.

Edited by:

Changhua Wang, Wuhan University, China

Reviewed by:

William Durante, University of Missouri, United States
Matilde Otero-Losada, National Council for Scientific and Technical Research (CONICET), Argentina
Muneyoshi Okada, Kitasato University, Japan  

Copyright: © 2019 Zhang, Deng, Jiang, Liu, Zhang, Cai, Tan, Huang, Jin, Liu and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Bin Liu, Guangzhou Medical University, Guangzhou, China, xmhoolv@163.com