title: Mammalian target of rapamycin overexpression antagonizes chronic hypoxia-triggered pulmonary arterial hypertension via the autophagic pathway.
abstract: Pulmonary arterial hypertension (PAH) is a progressive pulmonary vascular disorder with high morbidity and mortality, and is characterized by excessive growth of endothelial cells. Recently, the mammalian target of rapamycin (mTOR) has attracted increasing attention due to its potential as a therapeutic target against certain diseases associated with proliferative and metabolic abnormalities. However, the effect on mTOR on PAH has not yet been elucidated. In the present study, a marked downregulation of mTOR was observed in PAH patients. Following construction of a mouse model of PAH by chronic exposure to hypoxia, adenovirus-mediated upregulation of mTOR significantly attenuated right ventricular systolic pressure, right ventricular hypertrophy and wall thickness of pulmonary arterioles, indicating a protective effect of mTOR on PAH. Further analysis confirmed that mTOR overexpression inhibited autophagy triggered by hypoxia through blocking light chain 3 II expression and increasing p62 levels. In vitro, hypoxia enhanced the proliferation of human pulmonary artery endothelial cells (PAECs), which was markedly abrogated by mTOR overexpression. Of note, upregulation of mTOR inhibited the hypoxia-induced autophagy pathway, which contributed to cell proliferation, while silencing of autophagy by RNA interference with ATG5 significantly inhibited cell proliferation. In conclusion, the results of the present study suggested a potential protective effect of mTOR on the progression of PAH by suppressing PAEC proliferation through blocking the autophagic pathway. Therefore, the present study suggested that mTOR is a promising therapeutic agent against PAH.
authors.affiliation: The Cadre Ward, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Lingxia
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Emergency Medicine, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Xiaochuang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Emergency Medicine, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Emergency Medicine, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Qu
authors.affiliation: Department of Emergency Medicine, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Xinye
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Respiratory Diseases, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Manxiang
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Emergency Medicine, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Dang
authors.affiliation: Department of Emergency Medicine, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Emergency Medicine, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Emergency Medicine, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of Emergency Medicine, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Longfei
authors.initials: L
authors.lastname: Pan
authors.affiliation: Department of Emergency Medicine, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China.
authors.forename: Li
authors.initials: L
authors.lastname: Wan
mesh_terms: D000328:Adult; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071187:Autophagy-Related Protein 5; D015687:Cell Hypoxia / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D015536:Down-Regulation; D042783:Endothelial Cells; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000473:pathology*; D017380:Hypertrophy, Right Ventricular; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D011651:Pulmonary Artery / Q000166:cytology; D034622:RNA Interference; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000096:biosynthesis; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis*; D016278:Ventricular Function, Right
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; C118585:P62 protein, human; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases