PDF(Pubmed)
Abstract：
Blood-brain barrier (BBB) disruption after intracerebral hemorrhage (ICH) significantly induces neurological impairment. Previous studies showed that HDAC6 knockdown or TubA can protect the TNF-induced endothelial dysfunction. However, the role of HDAC6 inhibition on ICH-induced BBB disruption remains unknown.
Hemin-induced human brain microvascular endothelial cells (HBMECs) and collagenase-induced rats were employed to investigated the underlying impact of the HDAC6 inhibition in BBB lesion and neuronal dysfunction after ICH.
We found a significant decrease in acetylated α-tubulin during early phase of ICH. Both 25 or 40 mg/kg of TubA could relieve neurological deficits, perihematomal cell apoptosis, and ipsilateral brain edema in ICH animal model. TubA or specific siRNA of HDAC6 inhibited apoptosis and reduced the endothelial permeability of HBMECs. HDAC6 inhibition rescued the degradation of TJ proteins and repaired TJs collapses after ICH induction. Finally, the results suggested that the protective effects on BBB after ICH induction were exerted via upregulating the acetylated α-tubulin and reducing stress fiber formation.
Inhibition of HDAC6 expression showed beneficial effects against BBB disruption after experimental ICH, which suggested that HDAC6 could be a novel and promising target for ICH treatment.
Hemin-induced human brain microvascular endothelial cells (HBMECs) and collagenase-induced rats were employed to investigated the underlying impact of the HDAC6 inhibition in BBB lesion and neuronal dysfunction after ICH.
We found a significant decrease in acetylated α-tubulin during early phase of ICH. Both 25 or 40 mg/kg of TubA could relieve neurological deficits, perihematomal cell apoptosis, and ipsilateral brain edema in ICH animal model. TubA or specific siRNA of HDAC6 inhibited apoptosis and reduced the endothelial permeability of HBMECs. HDAC6 inhibition rescued the degradation of TJ proteins and repaired TJs collapses after ICH induction. Finally, the results suggested that the protective effects on BBB after ICH induction were exerted via upregulating the acetylated α-tubulin and reducing stress fiber formation.
Inhibition of HDAC6 expression showed beneficial effects against BBB disruption after experimental ICH, which suggested that HDAC6 could be a novel and promising target for ICH treatment.
摘要：
背景：脑出血（ICH）后血脑屏障（BBB）的破坏显著诱导神经功能缺损。先前的研究表明HDAC6敲低或TubA可以保护TNF诱导的内皮功能障碍。然而,HDAC6抑制对ICH诱导的BBB破坏的作用尚不清楚.
方法：使用Hemin诱导的人脑微血管内皮细胞（HBMECs）和胶原酶诱导的大鼠研究了HDAC6抑制对ICH后BBB病变和神经元功能障碍的潜在影响。
结果：我们发现在ICH早期阶段乙酰化α-微管蛋白显著减少。25mg/kg或40mg/kg的TubA都可以缓解神经功能缺损，血肿周围细胞凋亡,ICH动物模型中的同侧脑水肿。TubA或HDAC6的特异性siRNA抑制凋亡并降低HBMECs的内皮通透性。HDAC6抑制挽救了TJ蛋白的降解，修复的TJ在ICH诱导后崩溃。最后,结果表明，ICH诱导后对BBB的保护作用是通过上调乙酰化α-微管蛋白和减少应激纤维形成来实现的。
结论：抑制HDAC6表达对实验性ICH后BBB破坏显示出有益的作用，这表明HDAC6可能是ICH治疗的新靶点。
方法：使用Hemin诱导的人脑微血管内皮细胞（HBMECs）和胶原酶诱导的大鼠研究了HDAC6抑制对ICH后BBB病变和神经元功能障碍的潜在影响。
结果：我们发现在ICH早期阶段乙酰化α-微管蛋白显著减少。25mg/kg或40mg/kg的TubA都可以缓解神经功能缺损，血肿周围细胞凋亡,ICH动物模型中的同侧脑水肿。TubA或HDAC6的特异性siRNA抑制凋亡并降低HBMECs的内皮通透性。HDAC6抑制挽救了TJ蛋白的降解，修复的TJ在ICH诱导后崩溃。最后,结果表明，ICH诱导后对BBB的保护作用是通过上调乙酰化α-微管蛋白和减少应激纤维形成来实现的。
结论：抑制HDAC6表达对实验性ICH后BBB破坏显示出有益的作用，这表明HDAC6可能是ICH治疗的新靶点。
