Jangra Anshika, Choi Seung Ah, Koh Eun Jung, Moon Youn Joo, Wang Kyu-Chang, Phi Ji Hoon, Lee Ji Yeoun, Kim Seung-Ki
Division of Pediatric Neurosurgery, Seoul Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, Republic of Korea.
Department of Neurosurgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
Childs Nerv Syst. 2019 May;35(5):823-831. doi: 10.1007/s00381-019-04099-y. Epub 2019 Feb 27.
Moyamoya disease (MMD) is one of the most common causes of pediatric stroke. We found defective angiogenic function and downregulation of retinaldehyde dehydrogenase 2 (RALDH2) in MMD endothelial colony-forming cells (ECFCs). Downregulation of RALDH2 mRNA was caused by decreased binding of acetyl-histone H3 (Ac-H3) to the RALDH2 promoter. In this study, we evaluated the feasibility of using a histone deacetylase (HDAC) inhibitor, panobinostat, to upregulate RALDH2 expression and restore the angiogenic potential of MMD ECFCs.
ECFCs from healthy normal controls and patients with MMD were isolated and characterized. After panobinostat treatment, western blot, tube formation, and chromatin immunoprecipitation (ChIP) assays were conducted in vitro. A matrigel plug assay was performed in vivo.
Panobinostat increased the levels of Ac-H3 and Ac-H4 in both normal and MMD ECFCs but was much more effective in MMD ECFCs. Increased expression of RALDH2 by panobinostat was observed only in MMD ECFCs. Panobinostat increased the tube formation of both normal and MMD ECFCs in vitro and in vivo, but the effect was greater with MMD ECFCs.
We demonstrated that panobinostat increases the angiogenic ability of MMD ECFCs by regulating RALDH2 acetylation. Our results suggest that panobinostat might be a potent therapeutic option for MMD patients.
烟雾病（MMD）是小儿中风最常见的病因之一。我们发现MMD内皮集落形成细胞（ECFCs）存在血管生成功能缺陷及视黄醛脱氢酶2（RALDH2）表达下调。RALDH2 mRNA表达下调是由于乙酰化组蛋白H3（Ac-H3）与RALDH2启动子的结合减少所致。在本研究中，我们评估了使用组蛋白去乙酰化酶（HDAC）抑制剂帕比司他上调RALDH2表达并恢复MMD ECFCs血管生成潜能的可行性。
分离并鉴定健康正常对照者和MMD患者的ECFCs。帕比司他处理后，进行体外蛋白质免疫印迹、管腔形成及染色质免疫沉淀（ChIP）分析。进行体内基质胶栓分析。
帕比司他增加了正常和MMD ECFCs中Ac-H3和Ac-H4的水平，但对MMD ECFCs的作用更显著。仅在MMD ECFCs中观察到帕比司他使RALDH2表达增加。帕比司他在体外和体内均增加了正常和MMD ECFCs的管腔形成，但对MMD ECFCs的作用更大。
我们证明帕比司他通过调节RALDH2乙酰化增加了MMD ECFCs的血管生成能力。我们的结果表明帕比司他可能是MMD患者一种有效的治疗选择。
