Carolin Rommel1, Stephan Rösner1, Achim Lother1,2, Margareta Barg1, Martin Schwaderer1, Ralf Gilsbach1, Timo Bömicke1,3, Tilman Schnick1,4, Sandra Mayer1, Sophia Doll5, Michael Hesse6, Oliver Kretz7,8, Brigitte Stiller4, Franz-Josef Neumann3, Matthias Mann5, Markus Krane9,10,11, Bernd K Fleischmann6, Ursula Ravens12,13, Lutz Hein1,14. 1. 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.). 2. Heart Center, Cardiology and Angiology I, Faculty of Medicine (A.L.). 3. University of Freiburg, Germany; Heart Center, Cardiology and Angiology II, Freiburg-Bad Krozingen, Germany (T.B., F.-J.N.). 4. Heart Center, Congenital Heart Defects and Pediatric Cardiology, Faculty of Medicine (T.S., B.S.). 5. Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Martinsried, Germany (S.D., M.M.). 6. Institute of Physiology I, Life and Brain Center, Medical Faculty, University of Bonn, Germany (M.H., B.K.F.). 7. Medicine, Renal Division, Medical Center, Faculty of Medicine (O.K.). 8. III, Medicine, University Medical Center Hamburg-Eppendorf, Germany (O.K.). 9. Cardiovascular Surgery, German Heart Center Munich at the Technische Universität München, Germany (M.K.). 10. INSURE (Institute for Translational Cardiac Surgery), Cardiovascular Surgery, Munich, Germany (M.K.). 11. DZHK (German Center for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany (M.K.). 12. Institute of Experimental Cardiovascular Medicine, University Heart Center Freiburg-Bad Krozingen, Germany (U.R.). 13. Pharmacology and Toxicology, Medical Faculty, Technische Universität Dresden, Germany (U.R.). 14. BIOSS Centre for Biological Signaling Studies (L.H.).
Abstract
RATIONALE: 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. OBJECTIVE: 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. METHODS AND RESULTS: 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 Ca2+ 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. CONCLUSIONS: This study identifies ETV1 as an important component in the pathophysiology of atrial remodeling associated with atrial arrhythmias.
RATIONALE: 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. OBJECTIVE: 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. METHODS AND RESULTS: 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-deficientmice. 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 Ca2+ 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. CONCLUSIONS: This study identifies ETV1 as an important component in the pathophysiology of atrial remodeling associated with atrial arrhythmias.
Authors: Jeffrey D Steimle; Francisco J Grisanti Canozo; Minjun Park; Zachary A Kadow; Md Abul Hassan Samee; James F Martin Journal: JCI Insight Date: 2022-06-08
Authors: Lindsay J Young; Steve Antwi-Boasiako; Joel Ferrall; Loren E Wold; Peter J Mohler; Mona El Refaey Journal: Life Sci Date: 2022-04-03 Impact factor: 6.780
Authors: Chukwuemeka G Anene-Nzelu; Mick C J Lee; Wilson L W Tan; Albert Dashi; Roger S Y Foo Journal: Nat Rev Cardiol Date: 2021-08-11 Impact factor: 32.419
Authors: Alexandra J Trott; Ben J Greenwell; Tejas R Karhadkar; Natali N Guerrero-Vargas; Carolina Escobar; Ruud M Buijs; Jerome S Menet Journal: BMC Biol Date: 2022-03-03 Impact factor: 7.431
Authors: Naoko Yamaguchi; Junhua Xiao; Deven Narke; Devin Shaheen; Xianming Lin; Erik Offerman; Alireza Khodadadi-Jamayran; Akshay Shekhar; Alex Choy; Sojin Y Wass; David R Van Wagoner; Mina K Chung; David S Park Journal: Circulation Date: 2020-11-23 Impact factor: 29.690