Mesoglycan attenuates VSMC proliferation through activation of AMP-activated protein kinase and mTOR

Abstract

BACKGROUND: Vascular smooth muscle cells (VSMC) proliferation contributes significantly to intimal thickening in atherosclerosis and restenosis diseases. Platelet derived growth factor (PDGF) has been implicated in VSMC proliferation though the activation of multiple growth-promoting signals. Mesoglycan, a natural glycosaminoglycans preparation, is reported to show vascular protective effect. However, the mechanisms by which mesoglycan inhibits proliferation of VSMC are not fully understood. Here, we investigated whether mesoglycan exert therapeutic effect via AMP-activated protein kinase (AMPK) and its underlying mechanism.METHODS: We cultured VSMC with increasing doses of mesoglycan. AMPK activation was measured by western blot analysis and cell proliferation was measured by flow cytometry.RESULTS: Mesoglycan dose- and time- dependently increased the phosphorylation of AMPK (Thr(172)) and its upstream target, LKB1 (Ser(428)) and its downstream, ACC (Ser(79)) in VSMCs. Mesoglycan also blocked the PDGF-stimulated cell cycle progression through the G0/G1 arrest. AMPK DNα1, AMPK DNα2 or AMPK siRNA reduced the mesoglycan-mediated inhibition of VSMC proliferation. AMPK signaling activated by mesoglycan regulates mTOR phosphorylation which closely related to cell proliferation.CONCLUSION: These data suggest that mesoglycan-induced AMPK activation suppress the VSMC proliferation via mTOR-dependent mechanism and mesoglycan may have beneficial effects on vascular proliferative disorders such as atherosclerosis.