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Int. J. Mol. Sci. 2017, 18(1), 3; doi:10.3390/ijms18010003

Hypoxia Inducible Factor 1α Promotes Endogenous Adaptive Response in Rat Model of Chronic Cerebral Hypoperfusion

1
Department of Neurology, Zhongnan Hospital, Wuhan University, Donghu Road 169#, Wuhan 430071, China
2
Department of Neurology, Zhejiang Provincial People’s Hospital, Shangtang Road 158#, Hangzhou 310014, China
These two authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Katalin Prokai-Tatrai
Received: 4 October 2016 / Revised: 16 November 2016 / Accepted: 6 December 2016 / Published: 17 January 2017
(This article belongs to the Special Issue Neuroprotective Strategies 2016)
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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 endogenous HIF-1α to 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 down HIF-1α gene 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 of HIF-1α prior 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-1α knockdown also disrupts upregulation of regulated downstream genes. Our findings suggest that HIF-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. View Full-Text
Keywords: chronic cerebral hypoperfusion; hypoxia inducible factor 1α (HIF-1α); neuroprotective; cognition chronic cerebral hypoperfusion; hypoxia inducible factor 1α (HIF-1α); neuroprotective; cognition
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Yang, Y.; Ju, J.; Deng, M.; Wang, J.; Liu, H.; Xiong, L.; Zhang, J. Hypoxia Inducible Factor 1α Promotes Endogenous Adaptive Response in Rat Model of Chronic Cerebral Hypoperfusion. Int. J. Mol. Sci. 2017, 18, 3.

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