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.
Highlights
Diabetes mellitus is associated with increased risk of cardiovascular disease
Our findings clearly indicate that sodium tanshinone IIA silate (STS) stimulates AMPK and reverses impaired AMPK activation induced by HG conditions mimicking diabetes in vascular smooth muscle cell (VSMC)
These results suggest that STS inhibits high glucoseinduced VSMC proliferation by inducing cell cycle arrest at the G0/G1 phase
Summary
Diabetes mellitus is associated with increased risk of cardiovascular disease. Previous studies have reported that diabetic patients have a higher risk of developing atherosclerotic cardiovascular disease and higher rate of restenosis after percutaneous coronary intervention (PCI), compared to normal subjects [1]. AMPK activation leads to improved endothelial function [6], attenuation of myocardial ischemia injury in mice [7], and suppression of VSMC proliferation and migration as well as neointimal formation in a balloon injury rat model [8,9]. No studies to date have documented the effect of STS under high glucose conditions mimicking diabetes. Tanshinone IIA has been shown to enhance AMPK phosphorylation in endothelial cells [7], liver protein isolated from HF diet induced obese mice [13], L6 myotubes and skeletal muscle tissue of db/db mice [14]. We determined the effects of STS on VSMC proliferation and migration under high glucose conditions mimicking diabetes, and further investigated the underlying molecular mechanism, focusing on signaling pathway for AMPK activation
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