From the Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine (C.R., S.R., A.L., M.B., M.S., R.G., T.B., T.S., S.M., L.H.).
Heart Center, Cardiology and Angiology I, Faculty of Medicine (A.L.).
Circ Res. 2018 Aug 17;123(5):550-563. doi: 10.1161/CIRCRESAHA.118.313036.
Structural and electrophysiological remodeling of the atria are recognized consequences of sustained atrial arrhythmias, such as atrial fibrillation. The identification of underlying key molecules and signaling pathways has been challenging because of the changing cell type composition during structural remodeling of the atria.
Thus, the aims of our study were (1) to search for transcription factors and downstream target genes, which are involved in atrial structural remodeling, (2) to characterize the significance of the transcription factor ETV1 (E twenty-six variant 1) in atrial remodeling and arrhythmia, and (3) to identify ETV1-dependent gene regulatory networks in atrial cardiac myocytes.
The transcription factor ETV1 was significantly upregulated in atrial tissue from patients with permanent atrial fibrillation. Mice with cardiac myocyte-specific overexpression of ETV1 under control of the myosin heavy chain promoter developed atrial dilatation, fibrosis, thrombosis, and arrhythmia. Cardiac myocyte-specific ablation of ETV1 in mice did not alter cardiac structure and function at baseline. Treatment with Ang II (angiotensin II) for 2 weeks elicited atrial remodeling and fibrosis in control, but not in ETV1-deficient mice. To identify ETV1-regulated genes, cardiac myocytes were isolated and purified from mouse atrial tissue. Active cis-regulatory elements in mouse atrial cardiac myocytes were identified by chromatin accessibility (assay for transposase-accessible chromatin sequencing) and the active chromatin modification H3K27ac (chromatin immunoprecipitation sequencing). One hundred seventy-eight genes regulated by Ang II in an ETV1-dependent manner were associated with active cis-regulatory elements containing ETV1-binding sites. Various genes involved in Ca handling or gap junction formation ( Ryr2, Jph2, Gja5), potassium channels ( Kcnh2, Kcnk3), and genes implicated in atrial fibrillation ( Tbx5) were part of this ETV1-driven gene regulatory network. The atrial ETV1-dependent transcriptome in mice showed a significant overlap with the human atrial proteome of patients with permanent atrial fibrillation.
This study identifies ETV1 as an important component in the pathophysiology of atrial remodeling associated with atrial arrhythmias.
心房结构和电生理重构是持续性心房心律失常（如心房颤动）的公认后果。由于心房结构重构过程中细胞类型组成的变化，鉴定潜在的关键分子和信号通路一直具有挑战性。
因此，我们的研究目的是：（1）寻找参与心房结构重构的转录因子和下游靶基因；（2）研究转录因子 ETV1（E 二十六个变体 1）在心房重构和心律失常中的意义；（3）鉴定心房心肌细胞中 ETV1 依赖的基因调控网络。
在永久性心房颤动患者的心房组织中，转录因子 ETV1 显著上调。在肌球蛋白重链启动子控制下，心肌细胞特异性过表达 ETV1 的小鼠出现心房扩张、纤维化、血栓形成和心律失常。在小鼠中，心肌细胞特异性敲除 ETV1 不会改变心脏结构和功能的基线水平。用血管紧张素 II（Ang II）治疗 2 周，在对照组中引起心房重构和纤维化，但在 ETV1 缺陷型小鼠中则没有。为了鉴定 ETV1 调节的基因，从小鼠心房组织中分离和纯化心肌细胞。通过染色质可及性（转座酶可及性染色质测序）和活性染色质修饰 H3K27ac（染色质免疫沉淀测序）鉴定小鼠心房心肌细胞中的活性顺式调控元件。178 个受 Ang II 调控且依赖于 ETV1 的基因与包含 ETV1 结合位点的活性顺式调控元件相关。各种涉及 Ca 处理或缝隙连接形成的基因（Ryr2、Jph2、Gja5）、钾通道（Kcnh2、Kcnk3）和与心房颤动相关的基因（Tbx5）都是这个 ETV1 驱动的基因调控网络的一部分。在小鼠中，心房的 ETV1 依赖的转录组与永久性心房颤动患者的人类心房蛋白质组有显著的重叠。
本研究将 ETV1 确定为与心房心律失常相关的心房重构病理生理学的重要组成部分。
