Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway.
Inhibition of Connexin 43 reverses ox-LDL-mediated inhibition of autophagy in VSMC by inhibiting the PI3K/Akt/mTOR signaling pathway.
复制标题
抑制 Connexin 43 通过抑制 PI3K/Akt/mTOR 信号通路逆转 ox-LDL 介导的 VSMC 自噬抑制
作者：
Qin X;He W;Yang R;Liu L;Zhang Y;Li L;Si J;Li X;Ma K
氧化低密度脂蛋白（ox-LDL）可通过抑制血管平滑肌细胞（VSMC）自噬诱导VSMC形成泡沫细胞。这一过程加速了动脉粥样硬化（AS）的形成。连接蛋白43（Cx43）是VSMC中分布最广泛的连接蛋白，与自噬有关。然而，其作用机制和Cx43参与ox-LDL抑制的VSMC自噬仍不清楚。在用抑制剂（Cx43特异性抑制剂Gap 26和PI 3 K抑制剂LY 294002）预处理和用ox-LDL刺激原代VSMC之前，获得并鉴定原代VSMC。Ox-LDL不仅通过下调自噬相关蛋白（如Beclin 1、LC 3B、p62）抑制VSMC的自噬，而且通过上调Cx43蛋白水平抑制VSMC的自噬。在ox-LDL+ Gap 26组中加入Gap 26，自噬相关蛋白表达增加，脂滴堆积减少。这些结果提示，抑制Cx43可能通过增强VSMC的自噬水平和减轻脂质积聚而实现。ox-LDL可上调PI 3 K、AKT、mTOR的磷酸化水平，从而下调自噬相关蛋白的表达。然而，这一情况被Gap 26部分扭转。LY 294002还能降低ox-LDL诱导的VSMCs中Cx43的表达。抑制Cx43可能通过抑制PI 3 K/AKT/mTOR信号通路激活VSMC自噬以抑制泡沫细胞形成。
Oxidized low-density lipoproteins (ox-LDL) may induce foam cell formation from the vascular smooth muscle cell (VSMC) by inhibiting VSMC autophagy. This process accelerates the formation of atherosclerosis (AS). Connexin 43 (Cx43), which is the most widely distributed connexin in VSMC is associated with autophagy. However, the mechanism of action and the involvement of Cx43 in ox-LDL-inhibited VSMC autophagy remain unclear. The primary VSMC were obtained and identified, before primary VSMC were pretreated with an inhibitor (Cx43-specific inhibitor Gap26 and PI3K inhibitor LY294002) and stimulated with ox-LDL. Ox-LDL not only inhibited autophagy in VSMC via downregulation of autophagy-related proteins (such as Beclin 1, LC3B, p62), but also increased Cx43 protein levels. Then we added Gap26 to VSMC in the ox-LDL+Gap26 group, in which autophagy-related proteins were increased and the accumulation of lipid droplets was reduced. These result suggested that an enhanced level of autophagy and an alleviation of lipid accumulation might be caused by inhibiting Cx43 in VSMC. The phosphorylation levels of PI3K, AKT, mTOR were increased by ox-LDL, thus down-regulating autophagy-related proteins. However, this situation was partially reversed by the Gap26. Moreover, Cx43 expression were decreased by LY294002 in ox-LDL-induced VSMCs. Inhibiting Cx43 may activate VSMC autophagy to inhibit foam cell formation by inhibiting the PI3K/AKT/mTOR signaling pathway.
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DOI：
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发表时间：
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AUTOPHAGY: BIOLOGY AND DISEASES: BASIC SCIENCE
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