title: Nur77 downregulation triggers pulmonary artery smooth muscle cell proliferation and migration in mice with hypoxic pulmonary hypertension via the Axin2-β-catenin signaling pathway.
abstract: Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by remodeling of the pulmonary vasculature, including marked proliferation and reduced apoptosis of pulmonary artery smooth muscle cells (PASMCs). Members of the nuclear receptor 4A (NR4A) subfamily are involved in a variety of biological events, such as cell apoptosis, proliferation, inflammation, and metabolism. Activation of Nur77 (an orphan nuclear receptor that belongs to NR4A subfamily) has recently been reported to be as a beneficial agent in the treatment of cardiovascular and metabolic diseases. In the present study, we investigated the effects of NR4A on human PASMCs function in vitro and determined the underlying mechanisms. We found a robust expression of NR4A receptors in lung tissues of PAH patients and hypoxic mice but a highly significant downregulation within pulmonary arteries (PAs) as assessed by quantitative polymerase chain reaction, immunoblotting, and immunohistochemistry. In vitro, NR4A receptors were found significantly decreased in PASMCs derived from PAH patients. To explore the pathological effects of decreased Nur77 in PASMCs, PASMCs were transduced with siRNA against Nur77. The siRNA-mediated knockdown of Nur77 significantly augmented PASMCs proliferation and migration. In contrast, Nur77 overexpression prevented PASMCs from proliferation and migration. Mechanistically, overexpression of Axis inhibition protein 2 (Axin2) or inhibition of β-catenin signaling was shown to be responsible for Nur77 knockdown-induced proliferation of PASMCs. Following hypoxia-induced angiogenesis of the pulmonary artery in C57BL/6 mice, small-molecule Nur77 agonists-Octaketide Cytosporone B (Csn-B) can significantly decreased thickness of vascular wall and markedly attenuated the development of chronic hypoxia-induced PAH in vivo. Therefore, reconstitution of Nur77 levels represents a promising therapeutic option to prevent vascular remodeling processes.
authors.affiliation: Jiangsu Key Laboratory of Organ Transplantation, Wuxi People's Hospital Affiliated to Nanjing Medical University, PR China; Lung Transplant Group, Wuxi People's Hospital Affiliated to Nanjing Medical University, PR China. Electronic address: nxw912@126.com.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Nie
authors.affiliation: Jiangsu Key Laboratory of Organ Transplantation, Wuxi People's Hospital Affiliated to Nanjing Medical University, PR China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Tan
authors.affiliation: Jiangsu Key Laboratory of Organ Transplantation, Wuxi People's Hospital Affiliated to Nanjing Medical University, PR China.
authors.forename: Youai
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Department of Cardiothoracic Surgery, Wuxi People's Hospital Affiliated to Nanjing Medical University, PR China; Lung Transplant Group, Wuxi People's Hospital Affiliated to Nanjing Medical University, PR China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Mao
authors.affiliation: Department of Cardiothoracic Surgery, Wuxi People's Hospital Affiliated to Nanjing Medical University, PR China; Lung Transplant Group, Wuxi People's Hospital Affiliated to Nanjing Medical University, PR China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Wuxi People's Hospital Affiliated to Nanjing Medical University, PR China.
authors.forename: Guowei
authors.initials: G
authors.lastname: Qin
authors.affiliation: Jiangsu Key Laboratory of Organ Transplantation, Wuxi People's Hospital Affiliated to Nanjing Medical University, PR China.
authors.forename: Guirong
authors.initials: G
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Organ Transplantation, Wuxi People's Hospital Affiliated to Nanjing Medical University, PR China.
authors.forename: Chenyou
authors.initials: C
authors.lastname: Shen
authors.affiliation: Jiangsu Key Laboratory of Organ Transplantation, Wuxi People's Hospital Affiliated to Nanjing Medical University, PR China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Jiangsu Key Laboratory of Organ Transplantation, Wuxi People's Hospital Affiliated to Nanjing Medical University, PR China; Department of Cardiothoracic Surgery, Wuxi People's Hospital Affiliated to Nanjing Medical University, PR China; Lung Transplant Group, Wuxi People's Hospital Affiliated to Nanjing Medical University, PR China. Electronic address: cjy_wx@163.com.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D060466:Axin Protein / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000503:physiopathology*; D000860:Hypoxia; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics*; D011651:Pulmonary Artery / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage; D015398:Signal Transduction / Q000235:genetics; D066253:Vascular Remodeling / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C491761:AXIN2 protein, human; D060466:Axin Protein; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D034741:RNA, Small Interfering; D051176:beta Catenin
keywords: Axin2; Hypoxia; Orphan nuclear receptors Nur77; Pulmonary hypertension; β-Catenin