Quercetin induces autophagy via FOXO1-dependent pathways and autophagy suppression enhances quercetin-induced apoptosis in PASMCs in hypoxia
Quercetin induces autophagy via FOXO1-dependent pathways and autophagy suppression enhances quercetin-induced apoptosis in PASMCs in hypoxia
复制标题
槲皮素通过 FOXO1 依赖性途径诱导自噬，自噬抑制可增强缺氧条件下槲皮素诱导的 PASMC 细胞凋亡
DOI：
10.1016/j.freeradbiomed.2016.12.016
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发表时间：
2017-02-01
影响因子：
7.4
通讯作者：
Liu, Xiansheng
中科院分区：
文献类型：
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作者：
He, Yuanzhou;Cao, Xiaopei;Liu, Xiansheng
槲皮素是一种重要的膳食类黄酮，已被证明有可能逆转甚至预防肺动脉高压（PAH）的进展。然而，槲皮素对肺动脉平滑肌细胞（PASMCs）凋亡和自噬的影响尚未明确阐明。本研究发现，槲皮素在体外和体内缺氧条件下均能显著诱导PASMCs凋亡和自噬。此外，我们发现槲皮素增加FOXO 1（自噬调节的主要介质）表达和转录活性。此外，FOXO 1敲低siRNA抑制mTOR和4 E-BPI的磷酸化，这是P70-S6 K的下游，并显着阻断槲皮素诱导的自噬。我们还观察到FOXO 1介导的自噬是通过SESN 3而不是Rictor上调和mTOR抑制后实现的。自噬特异性抑制剂能显著增强槲皮素诱导的缺氧PASMCs凋亡。槲皮素联合自噬抑制治疗可增强槲皮素对缺氧相关PAH的治疗作用。槲皮素可通过FOXO 1-SENS 3-mTOR通路增强低氧诱导的PASMCs自噬。联合槲皮素和自噬抑制剂可能是治疗缺氧相关PAH的一种新的治疗策略。
Quercetin, an important dietary flavonoid has been demonstrated to potentially reverse or even prevent pulmonary arterial hypertension (PAH) progression. However, the effects of quercetin on apoptosis and autophagy in pulmonary arterial smooth muscle cells (PASMCs) have not yet been clearly elucidated. The current study found that quercetin significantly induce the apoptotic and autophagic capacities of PASMCs in vitro and in vivo in hypoxia. In addition, we found that quercetin increases FOXO1 (a major mediator in autophagy regulation) expression and transcriptional activity. Moreover, FOXO1 knockdown by siRNAs inhibited the phosphorylation of mTOR and 4E-BPI, which is downstream of P70-S6K, and markedly blocked quercetin-induced autophagy. We also observed that FOXO1-mediated autophagy was achieved via SESN3 not Rictor upregulation and after mTOR suppression. Furthermore, Treatment with autophagy-specific inhibitors could markedly enhance quercetin-induced apoptosis in PASMCs under hypoxia. Finally, quercetin in combination with autophagy inhibition treatment could enhance the therapeutic effects of quercetin in hypoxia-associated PAH in vivo. Taken together, quercetin could enhance hypoxia-induced autophagy through the FOXO1-SENS3-mTOR pathway in PASMCs. Combining quercetin and autophagy inhibitors may be a novel therapeutic strategy for treating hypoxia-associated PAH.