title: Quercetin induces autophagy via FOXO1-dependent pathways and autophagy suppression enhances quercetin-induced apoptosis in PASMCs in hypoxia.
abstract: 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.
authors.affiliation: Department of Respiratory Diseases, Tongji Hospital, Key Lab of Pulmonary Diseases of Health Ministry, Key Site of National Clinical Research Center for Respiratory Disease, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
authors.forename: Yuanzhou
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Respiratory Diseases, Tongji Hospital, Key Lab of Pulmonary Diseases of Health Ministry, Key Site of National Clinical Research Center for Respiratory Disease, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
authors.forename: Xiaopei
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Respiratory Diseases, Tongji Hospital, Key Lab of Pulmonary Diseases of Health Ministry, Key Site of National Clinical Research Center for Respiratory Disease, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
authors.forename: Pujian
authors.initials: P
authors.lastname: Guo
authors.affiliation: Department of Respiratory Diseases, Tongji Hospital, Key Lab of Pulmonary Diseases of Health Ministry, Key Site of National Clinical Research Center for Respiratory Disease, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Respiratory Diseases, Tongji Hospital, Key Lab of Pulmonary Diseases of Health Ministry, Key Site of National Clinical Research Center for Respiratory Disease, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Shang
authors.affiliation: Department of Respiratory Diseases, Tongji Hospital, Key Lab of Pulmonary Diseases of Health Ministry, Key Site of National Clinical Research Center for Respiratory Disease, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Respiratory Diseases, Tongji Hospital, Key Lab of Pulmonary Diseases of Health Ministry, Key Site of National Clinical Research Center for Respiratory Disease, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Respiratory Diseases, Tongji Hospital, Key Lab of Pulmonary Diseases of Health Ministry, Key Site of National Clinical Research Center for Respiratory Disease, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Respiratory Diseases, Tongji Hospital, Key Lab of Pulmonary Diseases of Health Ministry, Key Site of National Clinical Research Center for Respiratory Disease, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, China. Electronic address: doctorliu69@126.com.
authors.forename: Xiansheng
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D015870:Gene Expression / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D011651:Pulmonary Artery / Q000166:cytology; D011794:Quercetin / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D000071161:Forkhead Box Protein O1
chemical_list: D006360:Heat-Shock Proteins; D009419:Nerve Tissue Proteins; D011794:Quercetin; D058570:TOR Serine-Threonine Kinases; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C546845:mTOR protein, rat
keywords: Autophagy; FOXO1; Hypoxia; Pulmonary artery smooth muscle cells; Quercetin