All-Trans-Retinoic Acid Suppresses Neointimal Hyperplasia and Inhibits Vascular Smooth Muscle Cell Proliferation and Migration via Activation of AMPK Signaling Pathway.
机构：[1]Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China,[2]Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China,[3]Department of Internal Medicine, Huizhou Hospital of Traditional Chinese Medicine, Huizhou, China,[4]Department of Cardiology, Guangdong Second Provincial General Hospital, Guangzhou, China
The proliferation and migration of vascular smooth muscle cells (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 effects of ATRA. We found that treatment with ATRA significantly reduced neointimal hyperplasia in the left common carotid artery ligation mouse model. ATRA reduced the proliferation and migration of VSMC, A7r5 and HASMC cell lines. Our results also demonstrated that ATRA altered the expression of proliferation-related proteins, including CyclinD1, CyclinD3, CyclinA2, CDK2, CDK4, and CDK6 in VSMC. ATRA dose-dependently enhanced the phosphorylation level of AMPKα (Thr172) in the left common carotid artery of experimental mice. Also, the phosphorylation level of AMPKα in A7r5 and HASMC was significantly increased. 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) in A7r5 and HASMC. Notably, the inhibition of AMPKα by AMPK inhibitor (compound C) negated the protective effect of ATRA on VSMC proliferation in A7r5. Also, knockdown of AMPKα by siRNA partly abolished the anti-proliferative and anti-migratory effects of ATRA in HASMC. Molecular docking analysis showed that ATRA could dock to the 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 suppress VSMC proliferation and migration by direct activation of AMPK and inhibition of mTOR signaling.
基金：
This work was supported by National Natural Science
Foundation of China (Grant Nos. 81874418, 81774100, 81673949,
and 81503523), Guangdong Natural Science Foundation
(Grant Nos. 2016A020215167 and 2017A030313796), Science
and Technology Planning Project of Guangdong Province (Grant Nos. 2015A020211040 and 2017A020215115), the
education features innovative project of Guangdong Province
(Grant No. 2016KTSCX118), General Project from Guangzhou
Education Commission (Grant No. 1201610098), Medical
Scientific Research Foundation of Guangdong Province (Grant
No. A2017200), and Guangzhou Medical, Health Science, and
Technology Project (Grant No. 20181A011066).
第一作者机构：[1]Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China,[2]Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China,
共同第一作者：
通讯作者：
通讯机构：[1]Guangzhou Institute of Cardiovascular Disease, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China,[2]Department of Traditional Chinese Medicine, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China,
推荐引用方式(GB/T 7714)：
Jingzhi Zhang,Bo Deng,Xiaoli Jiang,et al.All-Trans-Retinoic Acid Suppresses Neointimal Hyperplasia and Inhibits Vascular Smooth Muscle Cell Proliferation and Migration via Activation of AMPK Signaling Pathway.[J].FRONTIERS IN PHARMACOLOGY.2019,10:doi:10.3389/fphar.2019.00485.
APA：
Jingzhi Zhang,Bo Deng,Xiaoli Jiang,Min Cai,Ningning Liu...&Shiming Liu.(2019).All-Trans-Retinoic Acid Suppresses Neointimal Hyperplasia and Inhibits Vascular Smooth Muscle Cell Proliferation and Migration via Activation of AMPK Signaling Pathway..FRONTIERS IN PHARMACOLOGY,10,
MLA：
Jingzhi Zhang,et al."All-Trans-Retinoic Acid Suppresses Neointimal Hyperplasia and Inhibits Vascular Smooth Muscle Cell Proliferation and Migration via Activation of AMPK Signaling Pathway.".FRONTIERS IN PHARMACOLOGY 10.(2019)
