Hypoxia Inducible Factor 1α Promotes Endogenous Adaptive Response in Rat Model of Chronic Cerebral Hypoperfusion.
Hypoxia Inducible Factor 1α Promotes Endogenous Adaptive Response in Rat Model of Chronic Cerebral Hypoperfusion.
复制标题
缺氧诱导因子 1 α 促进慢性脑低灌注大鼠模型的内源性适应性反应
DOI：
10.3390/ijms18010003
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发表时间：
2017-01-17
影响因子：
5.6
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Yang Y;Ju J;Deng M;Wang J;Liu H;Xiong L;Zhang J
缺氧诱导因子1α（Hypoxia inducible factor 1α，HIF-1α）是缺氧和缺血时基因表达的重要调节因子，目前被认为可根据应激的持续时间和严重程度调节促生存和促死亡反应。我们先前的研究表明，慢性全脑灌注不足（CCH）触发了大鼠海马中HIF-1α蛋白的长期积累。然而，稳定的HIF-1α在CCH中的作用尚不清楚。在这里，我们敲低内源性HIF-1α，以确定HIF-1α是否以及如何影响CCH的疾病过程和表型。将表达HIF-1α小发夹RNA的慢病毒注射到双侧海马和双侧脑室，以敲低海马和其他脑区的HIF-1α基因表达。永久性双侧颈总动脉闭塞，称为2-血管闭塞（2 VO），用于诱导大鼠的CCH。血管生成，氧化应激，脑组织病理学变化和认知功能进行了测试。2 VO前HIF-1α表达下调可加重CCH后4周的学习记忆障碍。在机械上，在CCH四周后还显示出大脑血管生成减少、氧化损伤增加以及皮质和海马的一些亚区中星形胶质细胞和小胶质细胞密度增加。此外，HIF-1α敲低还破坏了受调节的下游基因的上调。提示HIF-1α-在慢性脑血管病发病过程中具有保护脑组织免受氧化应激和炎症反应的作用。CCH过程中积累的HIF-1α介导内源性适应性过程以防御更严重的脑低灌注损伤，这可能提供治疗益处。
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.