title: Hypoxia-inducible factor 1α mediates neuroprotection of hypoxic postconditioning against global cerebral ischemia.
abstract: Hypoxia administered after transient global cerebral ischemia (tGCI) has been shown to induce neuroprotection in adult rats, but the underlying mechanisms for this protection are unclear. Here, we tested the hypothesis that hypoxic postconditioning (HPC) induces neuroprotection through upregulation of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF), and that this involves phosphatidylinositol-3-kinase (PI3K), p38 mitogen-activated protein kinase (p38 MAPK), and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) pathways. The expression of HIF-1α, VEGF, and cleaved caspase-9 were determined by immunohistochemistry and Western blot. As pharmacologic interventions, the HIF-1α inhibitor 2-methoxyestradiol (2ME2), PI3K inhibitor LY294002, p38 MAPK inhibitor SB203580, and MEK inhibitor U0126 were administered before HPC or after tGCI. We found that HPC maintained the higher expression of HIF-1α and VEGF and decreased cleaved caspase-9 levels in CA1 after tGCI. These effects were reversed by 2ME2 administered before HPC, and the neuroprotection of HPC was abolished. LY294002 and SB203580 decreased the expression of HIF-1α and VEGF after HPC, whereas U0126 increased HIF-1α and VEGF after tGCI. These findings suggested that HIF-1α exerts neuroprotection induced by HPC against tGCI through VEGF upregulation and cleaved caspase-9 downregulation, and that the PI3K, p38 MAPK, and MEK pathways are involved in the regulation of HIF-1α and VEGF.
authors.affiliation: From the Institute of Neurosciences and the Second Affiliated Hospital of Guangzhou Medical University Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China Yale School of Public Health, Yale University, New Haven, Connecticut (DL).
authors.forename: Tingna
authors.initials: T
authors.lastname: Zhu
authors.forename: Lixuan
authors.initials: L
authors.lastname: Zhan
authors.forename: Donghai
authors.initials: D
authors.lastname: Liang
authors.forename: Jiaoyue
authors.initials: J
authors.lastname: Hu
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Lu
authors.forename: Xinyong
authors.initials: X
authors.lastname: Zhu
authors.forename: Weiwen
authors.initials: W
authors.lastname: Sun
authors.forename: Liu
authors.initials: L
authors.lastname: Liu
authors.forename: En
authors.initials: E
authors.lastname: Xu
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit