title: Roles of HIF-1α, VEGF, and NF-κB in Ischemic Preconditioning-Mediated Neuroprotection of Hippocampal CA1 Pyramidal Neurons Against a Subsequent Transient Cerebral Ischemia.
abstract: Ischemic preconditioning (IPC) provides neuroprotection against subsequent severe ischemic insults by specific mechanisms. We tested the hypothesis that IPC attenuates post-ischemic neuronal death in the gerbil hippocampal CA1 region (CA1) throughout hypoxia inducible factor-1α (HIF-1α) and its associated factors such as vascular endothelial growth factor (VEGF) and nuclear factor-kappa B (NF-κB). Lethal ischemia (LI) without IPC increased expressions of HIF-1α, VEGF, and p-IκB-α (/and translocation of NF-κB p65 into nucleus) in CA1 pyramidal neurons at 12 h and/or 1-day post-LI; thereafter, their expressions were decreased in the CA1 pyramidal neurons with time and newly expressed in non-pyramidal cells (pericytes), and the CA1 pyramidal neurons were dead at 5-day post-LI, and, at this point in time, their immunoreactivities were newly expressed in pericytes. In animals with IPC subjected to LI (IPC/LI)-group), CA1 pyramidal neurons were well protected, and expressions of HIF-1α, VEGF, and p-IκB-α (/and translocation of NF-κB p65 into nucleus) were significantly increased compared to the sham-group and maintained after LI. Whereas, treatment with 2ME2 (a HIF-1α inhibitor) into the IPC/LI-group did not preserve the IPC-mediated increases of HIF-1α, VEGF, and p-IκB-α (/and translocation of NF-κB p65 into nucleus) expressions and did not show IPC-mediated neuroprotection. In brief, IPC protected CA1 pyramidal neurons from LI by upregulation of HIF-1α, VEGF, and p-IκB-α expressions. This study suggests that IPC increases HIF-1α expression in CA1 pyramidal neurons, which enhances VEGF expression and NF-κB activation and that IPC may be a strategy for a therapeutic intervention of cerebral ischemic injury.
authors: Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, 24341, South Korea.
authors: Jae-Chul
authors: JC
authors: Lee
authors: Bio-Safety Research Institute, College of Veterinary Medicine, Chonbuk National University, Iksan, Jeollabuk-do, 54596, South Korea.
authors: Hyun-Jin
authors: HJ
authors: Tae
authors: Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, 24341, South Korea.
authors: In Hye
authors: IH
authors: Kim
authors: Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, 24341, South Korea.
authors: Jeong Hwi
authors: JH
authors: Cho
authors: Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, 24341, South Korea.
authors: Tae-Kyeong
authors: TK
authors: Lee
authors: Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, 24252, South Korea.
authors: Joon Ha
authors: JH
authors: Park
authors: Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, 24252, South Korea.
authors: Ji Hyeon
authors: JH
authors: Ahn
authors: Department of Biomedical Science and Research Institute of Bioscience and Biotechnology, Hallym University, Chuncheon, 24252, South Korea.
authors: Soo Young
authors: SY
authors: Choi
authors: Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People's Republic of China.
authors: Hui Chen
authors: HC
authors: Bai
authors: Department of Physiology, College of Medicine, Hallym University, Chuncheon, 24252, South Korea.
authors: Bich-Na
authors: BN
authors: Shin
authors: Pharmacology & Toxicology Department, Shinpoong Pharmaceutical Co., Ltd., Ansan, 15610, South Korea.
authors: Geum-Sil
authors: GS
authors: Cho
authors: Department of Biochemistry and Molecular Biology, and Research Institute of Oral Sciences, College of Dentistry, Kangnung-Wonju National University, Gangneung, 25457, South Korea.
authors: Dae Won
authors: DW
authors: Kim
authors: Department of Food Science and Nutrition, Hallym University, Chuncheon, 24252, South Korea.
authors: Il Jun
authors: IJ
authors: Kang
authors: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 03722, South Korea.
authors: Young-Guen
authors: YG
authors: Kwon
authors: Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, 24341, South Korea.
authors: Young-Myeong
authors: YM
authors: Kim
authors: Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, 24341, South Korea. mhwon@kangwon.ac.kr.
authors: Moo-Ho
authors: http://orcid.org/0000-0002-7178-6501
authors: MH
authors: Won
authors: Department of Pediatrics, Chuncheon Sacred Heart Hospital, College of Medicine, Hallym University, Chunchen, 24253, South Korea. pedbej@hallym.or.kr.
authors: Eun Joo
authors: EJ
authors: Bae
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000473:pathology*; D005849:Gerbillinae; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D002546:Ischemic Attack, Transient / Q000378:metabolism / Q000473:pathology*; D019194:Ischemic Preconditioning; D008297:Male; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D000066829:Neuroprotection; D017966:Pyramidal Cells / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; D000072000:NF-KappaB Inhibitor alpha; D000077584:2-Methoxyestradiol
keywords: Delayed neuronal death; Hypoxia inducible factor-1α; Ischemia-reperfusion injury; Ischemic preconditioning; Nuclear factor-kappa B; Vascular endothelial growth factor