Department of Neurology, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, China.
Departments of Radiology and Neurology, Neuroprotection Research Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
J Neurochem. 2019 Apr;149(2):298-310. doi: 10.1111/jnc.14619. Epub 2018 Dec 3.
Histone deacetylase 3 (HDAC3), a member of class I HDAC, regulates a wide variety of normal and abnormal physiological functions. Recent experimental studies suggested that inhibition of HDAC3 may increase acetylation of certain key signaling regulating proteins such as peroxisome proliferator-activated receptor γ (PPARγ), which plays a crucial role in modulating cerebrovascular function and integrity. However, the role of HDAC3 inhibition in cerebrovascular endothelium function under pathological condition has not been fully investigated. In this study, we tested the hypothesis that inhibition of HDAC3 by RGFP966, a highly selective HDAC3 inhibitor, promotes PPARγ activation by enhancing its protein acetylation, resulting in protection of oxygen glucose deprivation and reoxygenation (OGD/R)-induced increase of transendothelial cell permeability. In cultured primary human brain microvascular endothelial cells, our experimental results show that OGD/R increases transendothelial cell permeability and down-regulates junction protein expression. While we also detected HDAC3 activity increase and PPARγ activity decline after OGD/R. However, treatment with RGFP966 significantly attenuated the OGD/R-induced increase of transendothelial cell permeability and down-regulation of tight junction protein Claudin-5. These effects were observed to be dependent on HDAC3 activity inhibition-mediated PPARγ protein acetylation/activation. Lastly, HDAC3 small interfering RNA mimics the protective effects of RGFP966 on human brain microvascular endothelial cells. Taken together, our data indicate that HDAC3 inhibition might comprise a new therapeutic target for reducing blood-brain barrier integrity disruption and vascular dysfunctions in neurological disorders.
组蛋白去乙酰化酶 3（HDAC3）是 I 类 HDAC 的成员，调节广泛的正常和异常生理功能。最近的实验研究表明，抑制 HDAC3 可能会增加某些关键信号调节蛋白的乙酰化，如过氧化物酶体增殖物激活受体γ（PPARγ），它在调节脑血管功能和完整性方面起着至关重要的作用。然而，HDAC3 抑制在病理条件下对脑血管内皮细胞功能的作用尚未得到充分研究。在这项研究中，我们通过实验验证了一个假设，即 RGFP966（一种高度选择性的 HDAC3 抑制剂）抑制 HDAC3 会通过增强其蛋白质乙酰化来促进 PPARγ 激活，从而保护氧葡萄糖剥夺和再氧合（OGD/R）引起的跨内皮细胞通透性增加。在培养的原代人脑微血管内皮细胞中，我们的实验结果表明，OGD/R 增加了跨内皮细胞通透性并下调了连接蛋白的表达。虽然我们还检测到 OGD/R 后 HDAC3 活性增加和 PPARγ 活性下降。然而，RGFP966 处理显著减弱了 OGD/R 诱导的跨内皮细胞通透性增加和紧密连接蛋白 Claudin-5 的下调。这些作用被观察到依赖于 HDAC3 活性抑制介导的 PPARγ 蛋白乙酰化/激活。最后，HDAC3 小干扰 RNA 模拟了 RGFP966 对人脑微血管内皮细胞的保护作用。综上所述，我们的数据表明，HDAC3 抑制可能成为减少神经紊乱中血脑屏障完整性破坏和血管功能障碍的新治疗靶点。
