title: Activation of HIF-1α and its downstream targets in rat hippocampus after long-term simulated microgravity exposure.
abstract: Microgravity has many detrimental impact on brain functions, however the underlying mechanism remain unclear. In present study, 28 days of tail-suspension (30°) was used to simulate microgravity in rats. We showed that oxidative stress in hippocampus was increased after 28 days of simulated microgravity in consideration of the decreased expression of NF-E2-related factor 2 (Nrf2) and the declined activities of total superoxide dismutase (T-SOD), CuZn-SOD, glutathione peroxidase (GSH-PX) and total antioxidant capacity (T-AOC). Using RNA-seq, we further investigated the effect of simulated microgravity on the expression of genes in hippocampus, and 849 genes were found to be differentially expressed. According to pathway analysis, the differentially expressed genes involved in cytoskeleton, metabolism, immunity, transcription regulation, etc. It is interesting to note that the differentially expressed genes were involved in hypoxia-associated pathway. In agreement with this, the expression of hypoxia induced factor-1α (HIF-1α), the master regulator of oxygen homeostasis, was significantly increased. Meanwhile, HIF-2α, a HIF-1α paralog, was elevated compared with the control group. The expression of pyruvate dehydrogenase kinase 1 (PDK1), lactate dehydrogenase A (LDHA) and vascular endothelial growth factor (VEGF), three well-defined downstream targets of HIF-1α, were up-regulated in hippocampus after 28 days of simulated microgravity exposure. Additionally, brain oxygen saturation (SO2) and blood flow analyzed by the tissue oxygen analysis system were also significantly reduced. These findings indicate that simulated microgravity might cause an alteration in oxygen homeostasis, providing novel insight into better understanding of how simulated microgravity affects the function of hippocampus and a new direction to the development of countermeasure for brain dysfunction during spaceflight (actual microgravity).
authors.affiliation: School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China; State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China. Electronic address: wangtingmei2003@163.com.
authors.forename: Tingmei
authors.initials: T
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China; Space Institute of Southern China (Shenzhen), Shamiao Road 4#, Pingdi Street, Longgang District, Shenzhen, 518117, China.
authors.forename: Hailong
authors.initials: H
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Lv
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China.
authors.forename: Guohua
authors.initials: G
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China.
authors.forename: Fengji
authors.initials: F
authors.lastname: Liang
authors.affiliation: School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China; State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China.
authors.forename: Yongliang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China; State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Research Center for Pharmacology and Toxicology, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100193, China.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China.
authors.forename: Hongqing
authors.initials: H
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China.
authors.forename: Guanghan
authors.initials: G
authors.lastname: Kan
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China.
authors.forename: Jianghui
authors.initials: J
authors.lastname: Xiong
authors.affiliation: School of Life Sciences, Northwestern Polytechnical University, Xi'an, 710072, China; State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China. Electronic address: yinghuidd@vip.sina.com.
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, 100094, China. Electronic address: linaqu@263.net.
authors.forename: Lina
authors.initials: L
authors.lastname: Qu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D020869:Gene Expression Profiling / Q000379:methods; D005979:Glutathione Peroxidase / Q000378:metabolism; D019417:Hindlimb Suspension / Q000379:methods*; D006624:Hippocampus / Q000098:blood supply / Q000378:metabolism*; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D014893:Weightlessness
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; D051267:NF-E2-Related Factor 2; C000631434:Pdk1 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D042461:Vascular Endothelial Growth Factor A; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D017346:Protein Serine-Threonine Kinases; D010100:Oxygen
keywords: HIF-1α; Hippocampus; Microgravity; Tail-suspension