Transcription factor early growth response-1 induction mediates inflammatory gene expression and brain damage following transient focal ischemia
Transcription factor early growth response-1 induction mediates inflammatory gene expression and brain damage following transient focal ischemia
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DOI：
10.1111/j.1471-4159.2008.05233.x
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发表时间：
2008-05-01
影响因子：
4.7
通讯作者：
Vemuganti, Raghu
中科院分区：
文献类型：
--
作者：
Tureyen, Kudret;Brooks, Nathaniel;Vemuganti, Raghu
早期生长反应-1（Egr 1）是一种在低氧条件下诱导表达的序列特异性转录因子（TF）。我们目前的报告，短暂的大脑中动脉闭塞（MCAO）导致Egr 1在成年小鼠和大鼠的大脑中的表达增加2小时和5天之间的再灌注与峰值增加8-12倍，在1天。当经历短暂MCAO和再灌注3天时，Egr 1-/-小鼠显示出比Egr 1 +/+同窝出生的小鼠显著更小的梗死（44.9 +/-8.4%，p < 0.05）和改善的神经功能。短暂MCAO后，与Egr 1 +/+小鼠相比，Egr 1-/-小鼠的脑显示较少的水积聚和减少的中性粒细胞浸润（42 +/-8%，p < 0.05）。与Egr 1 +/+小鼠相比，在Egr 1-/-小鼠的缺血后皮质中，活化的小胶质细胞/巨噬细胞的数量也显著较低（OX 42（+）细胞为53 +/-9%，p < 0.05，而ED 1（+）细胞为59 +/-11%）。此外，与Egr 1 +/+小鼠相比，Egr 1-/-小鼠脑中缺血后炎症基因表达不太明显。用靶向Egr 1的小干扰RNA阻止大脑Egr 1蛋白诱导降低了炎症基因表达，导致短暂MCAO大鼠的梗死面积缩小（40.2 +/-6.9%，p < 0.05），神经功能缺损减少。相反，腺病毒介导的Egr 1过表达后的短暂MCAO加重了大鼠的梗死体积（29 +/-5.3%，p < 0.05），并恶化了神经功能缺损。这些研究表明Egr 1是中风后炎症和神经元损伤的重要贡献者。
Early growth response-1 (Egr1) is a sequence-specific transcription factor (TF) which is induced under hypoxic conditions. We presently report that transient middle cerebral artery occlusion (MCAO) leads to increased expression of Egr1 in the brains of adult mice and rats between 2 h and 5 days of reperfusion with a peak increase of 8-12-fold at 1 day. When subjected to transient MCAO and 3 days of reperfusion, Egr1-/- mice showed significantly smaller infarcts (by 44.9 +/- 8.4%, p < 0.05) and improved neurological function than Egr1+/+ littermates. Following transient MCAO, brains of Egr1-/- mice showed less water accumulation and decreased neutrophil infiltration (by 42 +/- 8%, p < 0.05) compared to Egr1+/+ mice. The number of activated microglia/macrophages were also significantly lower (OX42(+) cells by 53 +/- 9%, p < 0.05 and ED1(+) cells by 59 +/- 11%) in the post-ischemic cortex of Egr1-/- mice compared to Egr1+/+ mice. In addition, post-ischemic inflammatory gene expression was less pronounced in the brains of Egr1-/- mice compared to Egr1+/+ mice. Preventing cerebral Egr1 protein induction with small interference RNAs that target Egr1 decreased inflammatory gene expression and led to smaller infarcts (by 40.2 +/- 6.9%, p < 0.05) and reduced neurological deficits in rats subjected to transient MCAO. Conversely, transient MCAO following adenoviral-mediated Egr1 over-expression exacerbated the infarct volume (by 29 +/- 5.3%, p < 0.05) and worsened the neurological deficits in rats. These studies indicate Egr1 as a significant contributor of inflammation and neuronal damage after stroke.