Multiple effects of 2ME2 and D609 on the cortical expression of HIF-1α and apoptotic genes in a middle cerebral artery occlusion-induced focal ischemia rat model
Multiple effects of 2ME2 and D609 on the cortical expression of HIF-1α and apoptotic genes in a middle cerebral artery occlusion-induced focal ischemia rat model
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DOI：
10.1111/j.1471-4159.2007.04652.x
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发表时间：
2007-09-01
影响因子：
4.7
通讯作者：
Zhou, Changman
中科院分区：
文献类型：
--
作者：
Chen, Chunhua;Hu, Qin;Zhou, Changman
尽管2-甲氧基紫杉醇（2 ME 2）和三环癸烷-9-基-黄原酸酯（D 609）对癌细胞具有多种作用，但在机制上，它们都下调缺氧诱导因子-1 α（HIF-1 α）和血管内皮生长因子（VEGF）。我们推测HIF-1 α作为促凋亡调节剂在脑缺血中起重要作用; 2 ME 2和D 609降低HIF-1 α和VEGF的水平，这可能有助于保护脑免受缺血损伤。将102只雄性Sprague-Dawley大鼠分为5组：假手术组、大脑中动脉闭塞（MCAO）组、MCAO +二甲基亚砜组、MCAO +2 ME 2组和MCAO + D 609组。2再灌注1h后腹腔注射ME 2和D 609。在24 h和7 d处死大鼠。24 h时，2 ME 2和D 609可降低脑梗死区HIF-1 α和VEGF的水平（酶联免疫吸附试验），抑制脑梗死区HIF-1 α、VEGF、BCL 2/腺病毒E1 B 19 kDa相互作用蛋白3（BNIP 3）和切割的caspase 3的表达（蛋白质印迹和免疫组织化学）。双荧光标记显示HIF-1 α阳性免疫反应物质与BNIP 3和末端脱氧核苷酸转移酶生物素-dUTP缺口末端标记共定位于神经元核内。在第7天，2 ME 2和D 609减少梗死体积（2，3，7-三苯基四氮唑氯化物）和血脑屏障外渗，降低死亡率并改善神经功能缺损。结论：2 ME 2和D 609通过抑制HIF-1 α表达、减弱VEGF的过度表达以避免血脑屏障破坏和通过BNIP 3途径抑制神经元凋亡，是脑缺血损伤的有效保护剂。
Despite 2-methoxyestradiol (2ME2) and tricyclodecan-9-yl-xanthogenate (D609) having multiple effects on cancer cells, mechanistically, both of them down-regulate hypoxia-inducible factor-1 alpha (HIF-1 alpha) and vascular endothelial growth factor (VEGF). We hypothesize HIF-1 alpha plays an essential role in cerebral ischemia as a pro-apoptosis regulator; 2ME2 and D609 decrease the levels of HIF-1 alpha and VEGF, that might contribute to protecting brain from ischemia injury. A total of 102 male Sprague-Dawley rats were split into five groups: sham, middle cerebral artery occlusion (MCAO), MCAO + dimethyl sulfoxide, MCAO + 2ME2, and MCAO + D609. 2ME2 and D609 were injected intraperitoneally 1 h after reperfusion. Rats were killed at 24 h and 7 days. At 24 h, 2ME2 and D609 reduce the levels of HIF-1 alpha and VEGF (enzyme-linked immunosorbent assay), depress the expression of HIF-1 alpha, VEGF, BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) and cleaved caspase 3 (western blot and immunohistochemistry) in the brain infarct area. Double fluorescence labeling shows HIF-1 alpha positive immunoreactive materials are co-localized with BNIP3 and terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling inside the nuclei of neurons. At 7 days, 2ME2 and D609 reduce the infarct volume (2,3,7-triphenyltetrazolium chloride) and blood-brain barrier extravasation, decrease the mortality and improve the neurological deficits. In conclusion, 2ME2 and D609 are powerful agents to protect brain from cerebral ischemic injury by inhibiting HIF-1 alpha expression, attenuating the superfluous expression of VEGF to avoid blood-brain barrier disruption and suppressing neuronal apoptosis via BNIP3 pathway.