title: Hypoxia Inducible Factor 1α Promotes Endogenous Adaptive Response in Rat Model of Chronic Cerebral Hypoperfusion.
abstract: Hypoxia inducible factor 1α (HIF-1α), a pivotal regulator of gene expression in response to hypoxia and ischemia, is now considered to regulate both pro-survival and pro-death responses depending on the duration and severity of the stress. We previously showed that chronic global cerebral hypoperfusion (CCH) triggered long-lasting accumulation of HIF-1α protein in the hippocampus of rats. However, the role of the stabilized HIF-1α in CCH is obscure. Here, we knock down endogenousHIF-1αto determine whether and how HIF-1α affects the disease processes and phenotypes of CCH. Lentivirus expressing HIF-1α small hairpin RNA was injected into the bilateral hippocampus and bilateral ventricles to knock downHIF-1αgene expression in the hippocampus and other brain areas. Permanent bilateral common carotid artery occlusions, known as 2-vessel occlusions (2VOs), were used to induce CCH in rats. Angiogenesis, oxidative stress, histopathological changes of the brain, and cognitive function were tested. Knockdown ofHIF-1αprior to 2VO significantly exacerbates the impairment of learning and memory after four weeks of CCH. Mechanically, reduced cerebral angiogenesis, increased oxidative damage, and increased density of astrocytes and microglia in the cortex and some subregions of hippocampus are also shown after four weeks of CCH. Furthermore,HIF-1αknockdown also disrupts upregulation of regulated downstream genes. Our findings suggest thatHIF-1α-protects the brain from oxidative stress and inflammation response in the disease process of CCH. Accumulated HIF-1α during CCH mediates endogenous adaptive processes to defend against more severe hypoperfusion injury of the brain, which may provide a therapeutic benefit.
authors.affiliation: Department of Neurology, Zhongnan Hospital, Wuhan University, Donghu Road 169#, Wuhan 430071, China. 200432180213@whu.edu.cn.|Department of Neurology, Zhejiang Provincial People's Hospital, Shangtang Road 158#, Hangzhou 310014, China. 200432180213@whu.edu.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Neurology, Zhongnan Hospital, Wuhan University, Donghu Road 169#, Wuhan 430071, China. julia88317@sohu.com.
authors.forename: Jieyang
authors.initials: J
authors.lastname: Ju
authors.affiliation: Department of Neurology, Zhongnan Hospital, Wuhan University, Donghu Road 169#, Wuhan 430071, China. minmin0jiejie@126.com.
authors.forename: Min
authors.initials: M
authors.lastname: Deng
authors.affiliation: Department of Neurology, Zhongnan Hospital, Wuhan University, Donghu Road 169#, Wuhan 430071, China. wangjing871207@126.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurology, Zhongnan Hospital, Wuhan University, Donghu Road 169#, Wuhan 430071, China. liuhui0070@gmail.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Neurology, Zhongnan Hospital, Wuhan University, Donghu Road 169#, Wuhan 430071, China. may.lixiong@gmail.com.
authors.forename: Li
authors.initials: L
authors.lastname: Xiong
authors.affiliation: Department of Neurology, Zhongnan Hospital, Wuhan University, Donghu Road 169#, Wuhan 430071, China. wdsjkx@163.com.
authors.forename: Junjian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D015153:Blotting, Western; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002540:Cerebral Cortex / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D003071:Cognition / Q000502:physiology; D004195:Disease Models, Animal; D015870:Gene Expression; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D008568:Memory / Q000502:physiology; D008840:Microfilament Proteins / Q000378:metabolism; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018613:Microscopy, Confocal; D034622:RNA Interference; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D065853:Spatial Learning / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008840:Microfilament Proteins; D042461:Vascular Endothelial Growth Factor A
keywords: chronic cerebral hypoperfusion; cognition; hypoxia inducible factor 1α (HIF-1α); neuroprotective