PMID- 30878387 OWN - NLM STAT- MEDLINE DCOM- 20190909 LR - 20191210 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 853 DP - 2019 Jun 15 TI - Tanshinone I inhibits vascular smooth muscle cell proliferation by targeting insulin-like growth factor-1 receptor/phosphatidylinositol-3-kinase signaling pathway. PG - 93-102 LID - S0014-2999(19)30176-1 [pii] LID - 10.1016/j.ejphar.2019.03.021 [doi] AB - Vascular smooth muscle cell (VSMC) proliferation plays a critical role in arterial remodeling during various vascular diseases including atherosclerosis and hypertension. Tanshinone I, a major component of Salvia miltiorrhiza, exerts protective effects against cardiovascular diseases. In this study, we investigated the effects of tanshinone I on VSMC proliferation, as well as the underlying mechanisms. We found that this compound inhibited the proliferation of VSMCs in a dose-dependent manner, based on 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) and 5-ethynyl-2'-deoxyuridine (EdU) assays. Western blotting demonstrated that tanshinone I inhibited the expression of proliferation-related proteins, including cyclin-dependent kinase 4 (CDK4), cyclin D3, and cyclin D1, in a dose-dependent manner. Molecular docking showed that this compound docked to the inhibitor-binding site of the insulin-like growth factor 1 (IGF-1) receptor (IGF-1R), and the binding energy between tanshinone I and IGF-1R was -9.021 kcal/mol. Molecular dynamic simulations showed that the IGF-1R-tanshinone I binding was stable. We also found that tanshinone I dose-dependently inhibited IGF-1R activation and its downstream molecules, insulin receptor substrate (IRS)-1, phosphatidylinositol-3-Kinase (PI3K), Akt, glycogen synthase kinase-3 beta (GSK3beta), mammalian target of rapamycin (mTOR), 70S6K, and ribosomal protein S6 (RPS6). Notably, activation of IGF-1R by recombinant IGF-1 rescued the activity of IGF-1R and its downstream molecules, and the proliferation of tanshinone I-treated VSMC. In addition, blocking PI3K signaling with LY294002 showed the important role of this pathway in tanshinone I-mediated suppression of VSMC proliferation. Collectively, these data demonstrated that tanshinone I might inhibit VSMC proliferation by inhibiting IGF-1R/PI3K signaling. CI - Copyright (c) 2019. Published by Elsevier B.V. FAU - Wu, Yu-Ting AU - Wu YT AD - School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. FAU - Bi, Yi-Ming AU - Bi YM AD - School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. FAU - Tan, Zhang-Bin AU - Tan ZB AD - School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. FAU - Xie, Ling-Peng AU - Xie LP AD - School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. FAU - Xu, Hong-Lin AU - Xu HL AD - School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. FAU - Fan, Hui-Jie AU - Fan HJ AD - School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. FAU - Chen, Hong-Mei AU - Chen HM AD - School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. FAU - Li, Jun AU - Li J AD - School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. FAU - Liu, Bin AU - Liu B AD - Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangzhou Institute of Cardiovascular Disease, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China. Electronic address: liubin@gzhmu.edu. FAU - Zhou, Ying-Chun AU - Zhou YC AD - School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China; Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: zhychun@smu.edu.cn. LA - eng PT - Journal Article DEP - 20190313 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Abietanes) RN - 03UUH3J385 (tanshinone) RN - EC 2.7.10.1 (Receptor, IGF Type 1) SB - IM MH - Abietanes/metabolism/*pharmacology MH - Cell Proliferation/drug effects MH - Humans MH - Molecular Docking Simulation MH - Molecular Dynamics Simulation MH - Muscle, Smooth, Vascular/*cytology MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Protein Conformation MH - Receptor, IGF Type 1/chemistry/*metabolism MH - Signal Transduction/*drug effects OTO - NOTNLM OT - Akt OT - GSK3beta OT - IGF-1R OT - PI3K OT - Proliferation OT - Tanshinone I OT - Vascular smooth muscle cell OT - mTOR EDAT- 2019/03/18 06:00 MHDA- 2019/09/10 06:00 CRDT- 2019/03/18 06:00 PHST- 2018/08/21 00:00 [received] PHST- 2019/03/03 00:00 [revised] PHST- 2019/03/12 00:00 [accepted] PHST- 2019/03/18 06:00 [pubmed] PHST- 2019/09/10 06:00 [medline] PHST- 2019/03/18 06:00 [entrez] AID - S0014-2999(19)30176-1 [pii] AID - 10.1016/j.ejphar.2019.03.021 [doi] PST - ppublish SO - Eur J Pharmacol. 2019 Jun 15;853:93-102. doi: 10.1016/j.ejphar.2019.03.021. Epub 2019 Mar 13.