Suppression of Hypoxia-Inducible Factor-1α and Its Downstream Genes Reduces Acute Hyperglycemia-Enhanced Hemorrhagic Transformation in a Rat Model of Cerebral Ischemia
Suppression of Hypoxia-Inducible Factor-1α and Its Downstream Genes Reduces Acute Hyperglycemia-Enhanced Hemorrhagic Transformation in a Rat Model of Cerebral Ischemia
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DOI：
10.1002/jnr.22361
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发表时间：
2010-07-01
影响因子：
4.2
通讯作者：
Zhang, John H.
中科院分区：
文献类型：
--
作者：
Chen, Chunhua;Ostrowski, Robert P.;Zhang, John H.
我们在大鼠局灶性脑缺血模型中评估了缺氧诱导因子-la（HIF-1 alpha）及其下游基因在急性高血糖诱导的出血性转化中的作用。将体重280-300 g的雄性Sprague-Dawley大鼠（n = 105）分为假手术组、大脑中动脉闭塞（MCAO）90 min组、MCAO加HIF-1 α α抑制剂2-甲氧基乙烯（2 ME 2）或3-（5 ′-羟甲基-2 ′-呋喃基）-1-苄基吲唑（YC-1）组。大鼠在MCAO前15分钟接受50%葡萄糖（6 ml/kg）腹腔注射。在再灌注开始时给予HIF-1 α et抑制剂。检查动物的神经功能缺损，并在MCAO后6、12、24和72小时处死。收集脑组织进行组织学、酶谱和蛋白质印迹分析。MCAO后缺血脑组织中HIF-1 α的表达增加，而HIF-1 α抑制剂则降低。此外，2 ME 2降低了血管内皮生长因子（VEGF）的表达和活性基质金属蛋白酶-2和-9（MMP-2/MMP-9）在同侧半球的升高。2 ME 2和YC-1均减少梗死体积并改善神经功能缺损。然而，只有2 ME 2减弱了缺血区域的出血性转化。总之，抑制HIF-1 α a及其下游基因可减轻脑梗死的出血性转化，改善局灶性脑缺血后的神经功能缺损。(C)2010 Wiley-Liss，Inc.
We evaluated a role of hypoxia-inducible factor-la (HIF-1 alpha) and its downstream genes in acute hypergly-cemia-induced hemorrhagic transformation in a rat model of focal cerebral ischemia. Male Sprague-Dawley rats weighing 280-300 g (n = 105) were divided into sham, 90 min middle cerebral artery occlusion (MCAO), MCAO plus HIF-1 alpha a inhibitors, 2-methoxyestradiol (2ME2) or 3-(5 '-hydroxymethy1-2 '-furyl)-1-benzylindazole (YC-1), groups. Rats received an injection of 50% dextrose (6 ml/kg intraperitoneally) at 15 min before MCAO. HIF-1 alpha et inhibitors were administered at the onset of reperfusion. The animals were examined for neurological deficits and sacrificed at 6, 12, 24, and 72 hr following MCAO. The cerebral tissues were collected for histology, zymography, and Western blot analysis. The expression of HIF-l alpha was increased in ischemic brain tissues after MCAO and reduced by HIF-la inhibitors. In addition, 2ME2 reduced the expression of vascular endothelial growth factor (VEGF) and the elevation of active matrix metalloproteinase-2 and -9 (MMP-2/MMP-9) in the ipsilateral hemisphere. Both 2ME2 and YC-1 reduced infarct volume and ameliorated neurological deficits. However, only 2ME2 attenuated hemorrhagic transformation in the ischemic territory. In conclusion, the inhibition of HIF-1 alpha a and its downstream genes attenuates hemorrhagic conversion of cerebral infarction and ameliorates neurological deficits after focal cerebral ischemia. (C) 2010 Wiley-Liss, Inc.