Department of Obstetrics, Gynecology, & Reproductive Sciences, Yale University School of Medicine, New Haven, CT, USA.
Department of Gynecology and Obstetrics, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
FASEB J. 2020 Jun;34(6):8625-8640. doi: 10.1096/fj.202000073RRRRR. Epub 2020 May 6.
While emerging evidence suggests the link between endothelial activation of TGF-β signaling, induction of endothelial-to-mesenchymal transition (EndMT), and cardiovascular disease (CVD), the molecular underpinning of this connection remains enigmatic. Here, we report aberrant expression of H19 lncRNA and TET1 in endothelial cells (ECs) of human atherosclerotic coronary arteries. Using primary human umbilical vein endothelial cells (HUVECs) and aortic endothelial cells (HAoECs) we show that TNF-α, a known risk factor for endothelial dysfunction and CVD, induces H19 expression which in turn activates TGF-β signaling and EndMT via a TET1-dependent epigenetic mechanism. We also show that H19 regulates TET1 expression at the posttranscriptional level. Further, we provide evidence that this H19/TET1-mediated regulation of TGF-β signaling and EndMT occurs in mouse pulmonary microvascular ECs in vivo under hyperglycemic conditions. We propose that endothelial activation of the H19/TET1 axis may play an important role in EndMT and perhaps CVD.
虽然有新的证据表明内皮细胞中 TGF-β 信号的激活、内皮细胞向间充质转化（EndMT）的诱导与心血管疾病（CVD）之间存在关联，但这一联系的分子基础仍然是个谜。在这里，我们报告了人类动脉粥样硬化性冠状动脉内皮细胞（ECs）中 H19 lncRNA 和 TET1 的异常表达。我们使用原代人脐静脉内皮细胞（HUVECs）和主动脉内皮细胞（HAoECs）表明，TNF-α，一种已知的内皮功能障碍和 CVD 的风险因素，诱导 H19 的表达，进而通过 TET1 依赖性表观遗传机制激活 TGF-β 信号和 EndMT。我们还表明，H19 在转录后水平调节 TET1 的表达。此外，我们提供的证据表明，在高血糖条件下，这种 H19/TET1 介导的 TGF-β 信号和 EndMT 的调节发生在体内的小鼠肺微血管内皮细胞中。我们提出内皮细胞中 H19/TET1 轴的激活可能在 EndMT 中甚至在 CVD 中发挥重要作用。
