Yu Jinyan, Ma Mengshi, Ma Zhongsen, Fu Jian
Department of Respiratory Medicine, The Second Hospital of Jilin University, Changchun, Jilin, P.R. China.
Center for Research on Environmental Disease, College of Medicine, University of Kentucky, Lexington, KY, USA.
Oncotarget. 2016 Aug 23;7(34):54714-54722. doi: 10.18632/oncotarget.10591.
Pro-inflammatory mediators such as TNF-α induce caspase activation in endothelial cells, which leads to degradation of cellular proteins, induction of apoptotic signaling, and endothelial cell dysfunction. New therapeutic agents that can inhibit caspase activation may provide protection against inflammatory injury to endothelial cells. In the present study, we examined the effects of selective histone deacetylase 6 (HDAC6) inhibition on TNF-α induced caspase 3 activation and cell-cell junction dysfunction in lung endothelial cells. We also assessed the protective effects of HDAC6 inhibition against lung inflammatory injury in a mouse model of endotoxemia. We demonstrated that selective HDAC6 inhibition or knockdown of HDAC6 expression was able to prevent caspase 3 activation in lung endothelial cells and maintain lung endothelial cell-cell junctions. Mice pre-treated with HDAC6 inhibitors exhibited decreased endotoxin-induced caspase 3 activation and reduced lung vascular injury as indicated by the retention of cell-cell junction protein VE-Cadherin level and alleviated lung edema. Collectively, our data suggest that HDAC6 inhibition is a potent therapeutic strategy against inflammatory injury to endothelial cells.
促炎介质如肿瘤坏死因子-α（TNF-α）可诱导内皮细胞中的半胱天冬酶激活，这会导致细胞蛋白降解、凋亡信号传导的诱导以及内皮细胞功能障碍。能够抑制半胱天冬酶激活的新型治疗药物可能为内皮细胞免受炎性损伤提供保护。在本研究中，我们研究了选择性组蛋白去乙酰化酶6（HDAC6）抑制对TNF-α诱导的肺内皮细胞中半胱天冬酶3激活和细胞间连接功能障碍的影响。我们还评估了HDAC6抑制在内毒素血症小鼠模型中对肺部炎性损伤的保护作用。我们证明，选择性HDAC6抑制或HDAC6表达的敲低能够预防肺内皮细胞中的半胱天冬酶3激活并维持肺内皮细胞间连接。用HDAC6抑制剂预处理的小鼠表现出内毒素诱导的半胱天冬酶3激活减少以及肺血管损伤减轻，这表现为细胞间连接蛋白血管内皮钙黏蛋白（VE-Cadherin）水平的保留和肺水肿的减轻。总体而言，我们的数据表明HDAC6抑制是一种针对内皮细胞炎性损伤的有效治疗策略。
