Xu Xingbo, Tan Xiaoying, Hulshoff Melanie S, Wilhelmi Tim, Zeisberg Michael, Zeisberg Elisabeth M
Department of Cardiology and Pneumology, University Medical Center of Göttingen, Georg-August University, Göttingen, Germany.
German Centre for Cardiovascular Research (DZHK), Göttingen, Germany.
FEBS Lett. 2016 Apr;590(8):1222-33. doi: 10.1002/1873-3468.12158. Epub 2016 Apr 21.
Cardiac fibrosis is integral in chronic heart disease, and one of the cellular processes contributing to cardiac fibrosis is endothelial-to-mesenchymal transition (EndMT). We recently found that hypoxia efficiently induces human coronary artery endothelial cells (HCAEC) to undergo EndMT through a hypoxia inducible factor-1α (HIF1α)-dependent pathway. Promoter hypermethylation of Ras-Gap-like protein 1 (RASAL1) has also been recently associated with EndMT progression and cardiac fibrosis. Our findings suggest that HIF1α and transforming growth factor (TGF)/SMAD signalling pathways synergistically regulate hypoxia-induced EndMT through both DNMT3a-mediated hypermethylation of RASAL1 promoter and direct SNAIL induction. The findings indicate that multiple cascades may be activated simultaneously to mediate hypoxia-induced EndMT.
心脏纤维化是慢性心脏病的一个主要特征，导致心脏纤维化的细胞过程之一是内皮-间充质转化（EndMT）。我们最近发现，缺氧通过缺氧诱导因子-1α（HIF1α）依赖性途径有效地诱导人冠状动脉内皮细胞（HCAEC）发生EndMT。Ras-Gap样蛋白1（RASAL1）的启动子高甲基化最近也与EndMT进展和心脏纤维化有关。我们的研究结果表明，HIF1α和转化生长因子（TGF）/SMAD信号通路通过DNMT3a介导的RASAL1启动子高甲基化和直接诱导SNAIL协同调节缺氧诱导的EndMT。这些发现表明，多个级联反应可能同时被激活，以介导缺氧诱导的EndMT。
