title: Increased Lung Ischemia-Reperfusion Injury in Aquaporin 1-Null Mice Is Mediated via Decreased Hypoxia-Inducible Factor 2α Stability.
abstract: Aquaporin (AQP) 1, a water channel protein expressed widely in vascular endothelia, has been shown to regulate cell migration, angiogenesis, and organ regeneration. Even though its role in the pathogenesis of lung ischemia-reperfusion (IR) injury has been defined, the functional role of AQP1 during long-term IR resolution remains to be clarified. Here, we found that AQP1 expression was increased at late time points (7-14 d) after IR and colocalized with endothelial cell (EC) marker CD31. Compared with IR in wild-type mice, IR in Aqp1(-/-) mice had significantly enhanced leukocyte infiltration, collagen deposition, and microvascular permeability, as well as inhibited angiogenic factor expression. AQP1 knockdown repressed hypoxia-inducible factor (HIF)-2α protein stability. HIF-2α overexpression rescued the angiogenic factor expression in pulmonary microvascular ECs with AQP1 knockdown exposed to hypoxia-reoxygenation. Furthermore, AQP1 knockdown suppressed cellular viability and capillary tube formation, and enhanced permeability in pulmonary microvascular ECs, which were partly rescued by HIF-2α overexpression. Thus, this study demonstrates that AQP1 deficiency delays long-term IR resolution, partly through repressing angiogenesis mediated by destabilizing HIF-2α. These results suggest that AQP1 participates in long-term IR resolution, at least in part by promoting angiogenesis.
authors.affiliation: 1 Department of Pulmonary Medicine, Huadong Hospital, and.|2 Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Ge
authors.affiliation: 1 Department of Pulmonary Medicine, Huadong Hospital, and.
authors.forename: Huili
authors.initials: H
authors.lastname: Zhu
authors.affiliation: 2 Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Nuo
authors.initials: N
authors.lastname: Xu
authors.affiliation: 2 Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Zhang
authors.affiliation: 2 Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Jiaxian
authors.initials: J
authors.lastname: Ou
authors.affiliation: 2 Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Guifang
authors.initials: G
authors.lastname: Wang
authors.affiliation: 2 Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Xiaocong
authors.initials: X
authors.lastname: Fang
authors.affiliation: 2 Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: 2 Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Song
authors.affiliation: 2 Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Chunxue
authors.initials: C
authors.lastname: Bai
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D051398:Aquaporin 1 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002448:Cell Adhesion; D002463:Cell Membrane Permeability; D002465:Cell Movement; D002470:Cell Survival; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D008168:Lung / Q000098:blood supply / Q000473:pathology*; D055370:Lung Injury / Q000378:metabolism / Q000473:pathology; D051379:Mice; D055806:Microvessels / Q000378:metabolism; D018919:Neovascularization, Physiologic; D055550:Protein Stability; D015427:Reperfusion Injury / Q000378:metabolism* / Q000473:pathology*; D015854:Up-Regulation; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D043925:Angiogenesis Inducing Agents; D051398:Aquaporin 1; D051792:Basic Helix-Loop-Helix Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1
keywords: acute lung injury; aquaporin 1; hypoxia-inducible factor 2α; lung ischemia–reperfusion injury