Abstract
Autophagy is increasingly being recognized as a critical determinant of vascular smooth muscle cell (VSMC) biology. Previously, we have demonstrated that c-Ski inhibits VSMC proliferation stimulated by transforming growth factor β (TGF-β), but it is not clear whether c-Ski has the similar protective role against other vascular injury factors and whether regulation of autophagy is involved in its protective effects on VSMC. Accordingly, in this study, rat aortic A10 VSMCs were treated with 40 µg/ml oxidized low-density lipoprotein (oxLDL) or 20 ng/ml platelet-derived growth factor (PDGF), both of which were autophagy inducers and closely related to the abnormal proliferation of VSMCs. Overexpression of c-Ski in A10 cells significantly suppressed the oxLDL- and PDGF- induced autophagy. This action of c-Ski resulted in inhibiting the cell proliferation, the decrease of contractile phenotype marker α-SMA expression while the increase of synthetic phenotype marker osteopontin expression stimulated by oxLDL or PDGF. Inversely, knockdown of c-Ski by RNAi enhanced the stimulatory effects of oxLDL or PDGF on A10 cell growth and phenotype transition. And further investigation found that inhibition of AKT phosphorylation to downregulate proliferating cell nuclear antigen (PCNA) expression, was involved in the regulation of autophagy and associated functions by c-Ski in the oxLDL- and PDGF-stimulated VSMCs. Collectively, c-Ski may play an important role in inhibiting autophagy to protect VSMCs against some harsh stress including oxLDL and PDGF.
Highlights
Vascular smooth muscle cells (VSMCs) are primary constituents of the blood vessel wall and essential regulators of vascular function
In the present study, we investigated the role of c-Ski in the autophagy and associated VSMC proliferation in rat aortic A10 cells treated with two primary atherogenesis and arterial restenosis regulators and identified VSMC autophagy inducible factors, oxidized lowdensity lipoprotein or platelet-derived growth factor (PDGF) [19,20]
Both ox-LDL and PDGF treatment increased LC3-II and Atg5 expressions significantly. These induction of LC3-II and Atg5 were markedly reduced by c-Ski, which to some extent mimicked the effects of autophagy inhibitor 3-MA in response to oxidized low-density lipoprotein (oxLDL)- and PDGF-induced autophagy in VSMCs
Summary
Vascular smooth muscle cells (VSMCs) are primary constituents of the blood vessel wall and essential regulators of vascular function. VSMCs change from a contractile phenotype to a synthetic phenotype, proliferate abnormally, synthesize extracellular matrix proteins and migrate to the intima, which play a key role in the intimal hyperplasia and progression of the vascular injury [1,2]. Multiple vascular injury risk factors, such as reactive species, cytokines and growth factors can induce autophagy in VSMC, which closely regulate the phenotype, proliferation, plasticity and survival of VSMC to affect the formation of intimal hyperplasia and the composition and stability of vascular lesions [9,10,11,12]
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