Quercetin induces autophagy via FOXO1-dependent pathways and autophagy suppression enhances quercetin-induced apoptosis in PASMCs in hypoxia

• Published in: Free radical biology & medicine 2017-02, Vol.103, p.165-176
• Main Authors: He, Yuanzhou, Cao, Xiaopei, Guo, Pujian, Li, Xiaochen, Shang, Huihui, Liu, Jin, Xie, Min, Xu, Yongjian, Liu, Xiansheng
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Autophagy; Autophagy - drug effects; Cell Hypoxia; Cells, Cultured; Drug Evaluation, Preclinical; FOXO1; Gene Expression - drug effects; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; Hypoxia; Male; Muscle, Smooth, Vascular - cytology; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - physiology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Oxidative Stress; Pulmonary Artery - cytology; Pulmonary artery smooth muscle cells; Quercetin; Quercetin - pharmacology; Rats, Sprague-Dawley; TOR Serine-Threonine Kinases - metabolism; Transcriptional Activation - drug effects
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2016.12.016

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. Graphical summary showing the mechanisms mediating the activation of FOXO1 in quercetin-induced apoptosis and autophagy signal cascade. [Display omitted] •Quercetin induce the apoptotic and autophagic capacities of cells in hypoxia.•Quercetin enhance hypoxia-induced autophagy through the FOXO1-SENS3-mTOR pathway.•Treatment with autophagy-specific inhibitors enhance quercetin-induced apoptosis.