title: Axis inhibition protein 2 deficiency leads to hypoxic pulmonary hypertension through β-catenin signaling pathway.
abstract: OBJECTIVE
  Pulmonary arterial hypertension (PAH) is characterized by increased vascular tone, altered vasoreactivity and vascular remodeling induced by smooth muscle cell proliferation. Similarities exist between cancer and PAH. Aberrant expression of the tumor suppressor protein is closely associated with PAH. Here, we tested the hypothesis that a tumor suppressor-axis inhibition protein 2 (Axin2) deficiency leads to PAH.
  
  
  RESULTS
  We measured right ventricular systolic pressure in Axin2 knockout mice and assessed the expression of Axin2 in patients. We found that Axin2 expression level was decreased in both mice exposed to chronic hypoxia and patients with PAH in remodeled pulmonary arterioles. Axin2 knockout mice showed elevated mean right ventricular systolic pressure and enhanced contraction in response to phenylephrine. An increase in the cross-sectional area of the vessels was occupied by the vessel wall, indicating pulmonary vascular remodeling. Furthermore, knocking down Axin2 with small interfering RNA inhibited apoptosis of pulmonary arterial smooth muscle cells (PASMCs). This inhibition was significantly abolished by β-catenin inhibitors, indicating that Axin2 through β-catenin increased vascular wall by inhibiting the apoptosis of PASMCs. Importantly, overexpression of Axin2 attenuates the development of hypoxia-induced PAH in mice.
  
  
  CONCLUSIONS
  Taken together, our study, for the first time, established that Axin2 plays a key role in the progression of PAH. We identified Axin2 as a novel mediator of pulmonary vasoconstriction and PASMC growth in hypoxia-mediated PAH. Our results suggest that downregulation of Axin2 in the pulmonary vasculature may be an underlying mechanism in the development of hypoxia-induced PAH.
authors.affiliation: aJiangsu Key Laboratory of Organ Transplantation bDepartment of Cardiothoracic Surgery cLung Transplant Group dDepartment of Anesthesiology eDepartment of Pathology, Wuxi People's Hospital, Nanjing Medical University, Wuxi, Jiangsu, PR China.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Nie
authors.forename: Guowei
authors.initials: G
authors.lastname: Qin
authors.forename: Wenjun
authors.initials: W
authors.lastname: Mao
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Chang
authors.forename: Dong
authors.initials: D
authors.lastname: Wei
authors.forename: Min
authors.initials: M
authors.lastname: Zhou
authors.forename: Bo
authors.initials: B
authors.lastname: Wu
authors.forename: Jingyu
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C491761:AXIN2 protein, human; D060466:Axin Protein; D051176:beta Catenin