title: Inhibiting HIF-1α by 2ME2 ameliorates early brain injury after experimental subarachnoid hemorrhage in rats.
abstract: Although hypoxia-inducible factor-1α (HIF-1α) has been extensively studied in brain injury following hypoxia-ischemia, the role of HIF-1α in early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains unclear. The present study was under taken to investigate a potential role of HIF-1α in EBI after SAH. Rats (n=60) were randomly divided into sham+vehicle, SAH+2-methoxyestradiol (2ME2), and SAH+vehicle groups. The SAH model was induced by endovascular perforation and all the rats were subsequently sacrificed at 24h after SAH. We found that treatment with 2ME2 suppressed the expression of HIF-1α, BNIP3 and VEGF and reduced cell apoptosis, blood-brain barrier (BBB) permeability, brain edema, and neurologic scores. Double fluorescence labeling revealed that HIF-1α was expressed predominantly in the nuclei of neurons and TUNEL-positive cells. Our work demonstrated that HIF-1α may play a role in EBI after SAH, causing cell apoptosis, BBB disruption, and brain edema by up-regulating its downstream targets, BNIP3 and VEGF. These effects were blocked by the HIF-1α inhibitor, 2ME2.
authors.affiliation: Department of Neurosurgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, No. 88 Jiefang road, Hangzhou 310009, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Wu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hu
authors.forename: Jingyin
authors.initials: J
authors.lastname: Chen
authors.forename: Feng
authors.initials: F
authors.lastname: Yan
authors.forename: Jianru
authors.initials: J
authors.lastname: Li
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Hangbo
authors.initials: H
authors.lastname: Mo
authors.forename: Chi
authors.initials: C
authors.lastname: Gu
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Gao
authors.initials: G
authors.lastname: Chen
mesh_terms: D000077584:2-Methoxyestradiol; D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy* / Q000209:etiology* / Q000378:metabolism; D004195:Disease Models, Animal; D057510:Endovascular Procedures / Q000379:methods; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D013345:Subarachnoid Hemorrhage / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: C505650:BNIP3 protein, rat; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D004958:Estradiol; D000077584:2-Methoxyestradiol
keywords: 2ME2; BNIP3; Early brain injury; Hypoxia-inducible factor-1α; Subarachnoid hemorrhage; VEGF