Department of Physiology and Pharmacology, Loma Linda University, 11041 Campus Street, Risley Hall Room 219, Loma Linda, CA 92354, USA.
J Neurosci Res. 2010 Jul;88(9):2046-55. doi: 10.1002/jnr.22361.
We evaluated a role of hypoxia-inducible factor-1alpha (HIF-1alpha) and its downstream genes in acute hyperglycemia-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-1alpha inhibitors, 2-methoxyestradiol (2ME2) or 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1), groups. Rats received an injection of 50% dextrose (6 ml/kg intraperitoneally) at 15 min before MCAO. HIF-1alpha 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-1alpha was increased in ischemic brain tissues after MCAO and reduced by HIF-1alpha 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-1alpha and its downstream genes attenuates hemorrhagic conversion of cerebral infarction and ameliorates neurological deficits after focal cerebral ischemia.
我们评估了缺氧诱导因子-1α（HIF-1α）及其下游基因在局灶性脑缺血大鼠模型中急性高血糖诱导出血性转化中的作用。雄性 Sprague-Dawley 大鼠，体重 280-300g（n=105），分为假手术组、90 分钟大脑中动脉闭塞（MCAO）组、MCAO 加 HIF-1α抑制剂、2-甲氧基雌二醇（2ME2）或 3-(5'-羟甲基-2'-呋喃基）-1-苯并吲哚（YC-1）组。大鼠在 MCAO 前 15 分钟腹腔内注射 50%葡萄糖（6ml/kg）。HIF-1α 抑制剂在再灌注开始时给予。在 MCAO 后 6、12、24 和 72 小时对动物进行神经功能缺损检查并进行安乐死。采集脑组织进行组织学、酶谱和 Western blot 分析。HIF-1α 在 MCAO 后缺血性脑组织中表达增加，被 HIF-1α 抑制剂减少。此外，2ME2 降低了血管内皮生长因子（VEGF）的表达，并降低了同侧半脑活性基质金属蛋白酶-2 和 -9（MMP-2/MMP-9）的水平。2ME2 和 YC-1 均减少了梗死体积并改善了神经功能缺损。然而，只有 2ME2 减轻了缺血区的出血性转化。总之，抑制 HIF-1α 及其下游基因可减轻局灶性脑缺血后脑梗死的出血性转化并改善神经功能缺损。
