Department of Pathophysiology and High Altitude Physiology, College of High Altitude Military Medicine, Chongqing 400038, China.
Cardiovasc Res. 2013 Dec 1;100(3):363-73. doi: 10.1093/cvr/cvt214. Epub 2013 Sep 16.
Establishment of an inflammatory milieu following elevated leukocyte adhesion to the vascular endothelium, which is mediated by transcriptional activation of cell adhesion molecules (CAMs), contributes to the pathogenesis of chronic hypoxia-induced pulmonary hypertension (HPH). The epigenetic switch that dictates CAM transactivation in response to hypoxia in endothelial cells leading up to HPH is not fully appreciated.
We report here that brahma-related gene 1 (Brg1) and brahma (Brm), two catalytic components of the mammalian chromatin remodelling complex, were induced in cultured endothelial cells challenged with hypoxia in vitro as well as in pulmonary arteries in an animal model of HPH. Over-expression of Brg1/Brm enhanced, while the depletion of Brg1/Brm attenuated, CAM transactivation and adhesion of leukocytes. Endothelial-specific deletion of Brg1/Brm ameliorated vascular inflammation and HPH in mice. Chromatin immunoprecipitation (ChIP) and re-ChIP assays revealed that hypoxia up-regulated the occupancies of Brg1 and Brm on CAM promoters in a nuclear factor κB (NF-κB) -dependent manner. Finally, Brg1 and Brm activated CAM transcription by altering the chromatin structure surrounding the CAM promoters.
Our data suggest that Brg1 provides the crucial epigenetic link to hypoxia-induced CAM induction and leukocyte adhesion that engenders endothelial malfunction and pathogenesis of HPH. As such, targeting Brg1 in endothelial cells may yield promising strategies in the intervention and/or prevention of HPH.
白细胞黏附于血管内皮后会引发炎症微环境，这一过程受到细胞黏附分子（CAM）转录激活的介导，从而导致慢性低氧诱导的肺动脉高压（HPH）的发生。目前，人们对于内皮细胞中导致 HPH 的低氧反应性 CAM 转激活的表观遗传开关还没有完全了解。
我们在此报告，在体外低氧刺激的培养内皮细胞以及 HPH 动物模型的肺动脉中，Brahma 相关基因 1（Brg1）和 Brama（Brm）这两种哺乳动物染色质重塑复合物的催化亚基被诱导表达。Brg1/Brm 的过表达增强了 CAM 的转激活和白细胞的黏附，而 Brg1/Brm 的耗竭则减弱了 CAM 的转激活和白细胞的黏附。内皮细胞特异性 Brg1/Brm 缺失可改善小鼠的血管炎症和 HPH。染色质免疫沉淀（ChIP）和再 ChIP 实验表明，低氧以核因子 κB（NF-κB）依赖的方式上调了 Brg1 和 Brm 在 CAM 启动子上的占有率。最后，Brg1 和 Brm 通过改变 CAM 启动子周围的染色质结构来激活 CAM 转录。
我们的数据表明，Brg1 提供了与低氧诱导的 CAM 诱导和白细胞黏附相关的关键表观遗传联系，从而导致内皮功能障碍和 HPH 的发病机制。因此，针对内皮细胞中的 Brg1 可能是干预和/或预防 HPH 的有前途的策略。
