title: Sodium tanshinone IIA silate inhibits high glucose-induced vascular smooth muscle cell proliferation and migration through activation of AMP-activated protein kinase.
abstract: The proliferation of vascular smooth muscle cells may perform a crucial role in the pathogenesis of diabetic vascular disease. AMPK additionally exerts several salutary effects on vascular function and improves vascular abnormalities. The current study sought to determine whether sodium tanshinone IIA silate (STS) has an inhibitory effect on vascular smooth muscle cell (VSMC) proliferation and migration under high glucose conditions mimicking diabetes without dyslipidemia, and establish the underlying mechanism. In this study, STS promoted the phosphorylation of AMP-activated protein kinase (AMPK) at T172 in VSMCs. VSMC proliferation was enhanced under high glucose (25 mM glucose, HG) versus normal glucose conditions (5.5 mM glucose, NG), and this increase was inhibited significantly by STS treatment. We utilized western blotting analysis to evaluate the effects of STS on cell-cycle regulatory proteins and found that STS increased the expression of p53 and the Cdk inhibitor, p21, subsequent decreased the expression of cell cycle-associated protein, cyclin D1. We further observed that STS arrested cell cycle progression at the G0/G1 phase. Additionally, expression and enzymatic activity of MMP-2, translocation of NF-κB, as well as VSMC migration were suppressed in the presence of STS. Notably, Compound C (CC), a specific inhibitor of AMPK, as well as AMPK siRNA blocked STS-mediated inhibition of VSMC proliferation and migration. We further evaluated its potential for activating AMPK in aortas in animal models of type 2 diabetes and found that Oral administration of STS for 10 days resulted in activation of AMPK in aortas from ob/ob or db/db mice. In conclusion, STS inhibits high glucose-induced VSMC proliferation and migration, possibly through AMPK activation. The growth suppression effect may be attributable to activation of AMPK-p53-p21 signaling, and the inhibitory effect on migration to the AMPK/NF-κB signaling axis.
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Wen-yu
authors.initials: WY
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xin-bo
authors.initials: XB
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yu-zhou
authors.initials: YZ
authors.lastname: Gui
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xi-lan
authors.initials: XL
authors.lastname: Tang
authors.affiliation: Carefree Pharmaceutical Co., Ltd, Nanjing, China.
authors.forename: Yin-lin
authors.initials: YL
authors.lastname: Qin
authors.affiliation: Carefree Pharmaceutical Co., Ltd, Nanjing, China.
authors.forename: Mei
authors.initials: M
authors.lastname: Su
authors.affiliation: Carefree Pharmaceutical Co., Ltd, Nanjing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yi-ping
authors.initials: YP
authors.lastname: Wang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000201:enzymology; D015153:Blotting, Western; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D005947:Glucose / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008820:Mice, Obese; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D061251:Primary Cell Culture; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D013912:Threonine / Q000378:metabolism
chemical_list: D045784:Abietanes; D004365:Drugs, Chinese Herbal; C021751:tanshinone; D013912:Threonine; D055372:AMP-Activated Protein Kinases; D005947:Glucose
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