Aqp-1 Gene Knockout Attenuates Hypoxic Pulmonary Hypertension of Mice

作者：Liu, Mingcheng; Liu, Qiwang; Pei, Yandong; Gong, Miaomiao; Cui, Xiaolin; Pan, Jinjin; Zhang, Yunlong; Liu, Yang; Liu, Ying; Yuan, Xiaocheng; Zhou, Haoran; Chen, Yiying; Sun, Jian; Wang, Lin; Zhang, Xiya; Wang, Rui; Li, Shao; Cheng, Jizhong; Ding, Yanchun^*; Ma, Tonghui^*; Yuan, Yuhui^*

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2019, 39(1): 48-62.

DOI：10.1161/ATVBAHA.118.311714

• apoptosis
• aquaporin 1
• hypertension
• hypoxia
• vascular remodeling

Objective-Hypoxic pulmonary hypertension (HPH) is characterized by proliferative vascular remodeling. Abnormal pulmonary artery smooth muscle cells proliferation and endothelial dysfunction are the primary cellular bases of vascular remodeling. AQP1 (aquaporin-1) is regulated by oxygen level and has been observed to play a role in the proliferation and migration of pulmonary artery smooth muscle cells. The role of AQP1 in HPH pathogenesis has not been directly determined to date. To determine the possible roles of AQP1 in the pathogenesis of HPH and explore its possible mechanisms.
Approach and Results-Aqp1 knockout mice were used, and HPH model was established in this study. Primary pulmonary artery smooth muscle cells, primary mouse lung endothelial cells, and lung tissue sections from HPH model were used. Immunohistochemistry, immunofluorescence and Western blot, cell cycle, apoptosis, and migration analysis were performed in this study. AQP1 expression was upregulated by chronic hypoxia exposure, both in pulmonary artery endothelia and medial smooth muscle layer of mice. Aqp1 deficiency attenuated the elevation of right ventricular systolic pressures and mitigated pulmonary vascular structure remodeling. AQP1 deletion reduced abnormal cell proliferation in pulmonary artery and accompanied with accumulation of HIF (hypoxia-inducible factor). In vitro, Aqp1 deletion reduced hypoxia-induced proliferation, apoptosis resistance, and migration ability of primary cultured pulmonary artery smooth muscle cells and repressed HIF-1 alpha protein stability. Furthermore, Aqp1 deficiency protected lung endothelial cells from apoptosis in response to hypoxic injury.
Conclusions-Our data showed that Aqp1 deficiency could attenuate hypoxia-induced vascular remodeling in the development of HPH. AQP1 may be a potential target for pulmonary hypertension treatment.

• 出版日期2019-1
• 单位大连医科大学