Changes in Levels of Hypoxia-Induced Mediators in Rat Hippocampus During Chronic Cerebral Hypoperfusion
Changes in Levels of Hypoxia-Induced Mediators in Rat Hippocampus During Chronic Cerebral Hypoperfusion
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DOI：
10.1007/s11064-013-1158-1
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发表时间：
2013-09
影响因子：
4.4
通讯作者：
Ying Yang;Junjian Zhang;Hui Liu;Jing Wang;Jiawei Xin;Min Deng
中科院分区：
文献类型：
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作者：
Ying Yang;Junjian Zhang;Hui Liu;Jing Wang;Jiawei Xin;Min Deng
缺氧诱导因子（HIF）介导的信号通路是一种适应性和保护性机制，由缺氧、缺血和其他病理生理条件触发。HIF-1α和下游基因的表达在缺血性卒中中上调，其中一些基因是促凋亡基因，而另一些基因是促存活基因。然而，有趣的是，HIF-1α激活的影响在急性脑缺血的早期和晚期是不同的，并且这些差异可能取决于缺氧的持续时间和严重程度。因此，在本研究中，我们研究了HIF-1α激活在慢性脑低灌注中的作用，这在痴呆的发展中起着重要作用。采用永久性双侧颈总动脉阻断（2 VO）方法建立大鼠慢性全脑低灌注模型。分别于2 VO后0 h、12 h、24 h、3 d、7 d、14 d、28 d、42 d、56 d检测HIF-1α蛋白表达及下游基因转录水平。缺氧诱导因子-1 α在缺血后12 h即开始升高，并持续升高至少56 d。有趣的是，促凋亡基因（Bcl-2/腺病毒EIB 19 kDa相互作用蛋白3、NADPH氧化酶激活剂1和NIP 3样蛋白X）和促存活基因（血管内皮生长因子、葡萄糖转运蛋白1）的mRNA水平在2 VO后的早期阶段上调，随后逐渐下降至基线/对照水平。因此，HIF-1α在慢性脑灌注不足期间持续增加，而促凋亡和促存活下游基因仅在2 VO后早期上调。这种基因表达的不匹配可能导致高表达的HIF-1α在脑低灌注慢性期缺乏保护作用。
The hypoxia-inducible factor (HIF)-mediated signaling pathway is an adaptive and protective mechanism that is triggered by hypoxia, ischemia, and other pathophysiological conditions. The expression of HIF-1α and downstream genes, some of which are pro-apoptotic whereas others are pro-survival, is up-regulated in ischemic stroke. Interestingly, however, the effects of HIF-1α activation are different in the early and late stages of acute cerebral ischemia, and these differences may depend on the duration and severity of hypoxia. Therefore, in the present study, we investigated the effect of HIF-1α activation in chronic cerebral hypoperfusion, which plays an important role in the development of dementia. Permanent bilateral common carotid artery occlusion (2VO) was used to induce chronic global cerebral hypoperfusion in rats. The expression of HIF-1α protein and the transcription of downstream genes were measured at different time points, including 0 h, 12 h, 24 h, 3 days, 7 days, 14 days, 28 days, 42 days, and 56 days after 2VO. HIF-1α increased as early as 12 h after the occlusion and remained high for at least 56 days. Interestingly, mRNA levels of both pro-apoptotic (Bcl-2/adenovirus EIB 19 kDa-interacting protein 3, NADPH oxidase activator 1, and NIP3-like protein X) and pro-survival (vascular endothelial growth factor, glucose transporter-1) genes were up-regulated at the early stage after 2VO, followed by a gradual decline to baseline/control levels. Thus, HIF-1α increased consistently during chronic cerebral hypoperfusion, whereas both pro-apoptotic and pro-survival downstream genes were up-regulated only early after 2VO. This mismatch in gene expression may contribute to the lack of a protective effect of highly expressed HIF-1α during the chronic stage of cerebral hypoperfusion.