Sodium tanshinone IIA silate inhibits high glucose-induced vascular smooth muscle cell proliferation and migration through activation of AMP-activated protein kinase

• Published in: PloS one 2014-04, Vol.9 (4), p.e94957
• Main Authors: Wu, Wen-yu, Yan, Hong, Wang, Xin-bo, Gui, Yu-zhou, Gao, Fei, Tang, Xi-lan, Qin, Yin-lin, Su, Mei, Chen, Tao, Wang, Yi-ping
• Format: Article
• Language: English
• Subjects: Abietanes - pharmacology; Abnormalities; Activation; AMP; AMP-activated protein kinase; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Analysis; Animal models; Animals; Aorta - enzymology; Biology and Life Sciences; Blotting, Western; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell migration; Cell Movement - drug effects; Cell proliferation; Cell Proliferation - drug effects; Circulatory system; Cyclin D1; Cyclin-dependent kinase inhibitor p21; Diabetes mellitus; Diabetes Mellitus, Type 2 - enzymology; Diabetes Mellitus, Type 2 - genetics; Dose-Response Relationship, Drug; Drugs, Chinese Herbal - pharmacology; Dyslipidemia; Enzymatic activity; Enzyme Activation - drug effects; Flow Cytometry; G1 phase; Gelatinase A; Glucose; Glucose - pharmacology; Glucose metabolism; GTP-binding protein; Inhibitors; Kinases; Male; Medicine and Health Sciences; Mice; Mice, Mutant Strains; Mice, Obese; Mimicry; Muscle, Smooth, Vascular - cytology; Muscles; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; NF-κB protein; Oral administration; p53 Protein; Pathogenesis; Phosphorylation; Phosphorylation - drug effects; Physiological aspects; Primary Cell Culture; Protein kinases; Proteins; Rats, Sprague-Dawley; Regulatory proteins; Research and Analysis Methods; RNA Interference; Rodents; Signaling; Smooth muscle; Sodium; Threonine - metabolism; Translocation; Tumor proteins; Vascular diseases; Western blotting
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0094957

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.