دورية أكاديمية
WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling
| العنوان: | WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling |
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| المؤلفون: | Chen, Huimei, Moreno-Moral, Aida, Pesce, Francesco, Devapragash, Nithya, Mancini, Massimiliano, Heng, Ee Ling, Rotival, Maxime, Srivastava, Prashant, K, Harmston, Nathan, Shkura, Kirill, Rackham, Owen, J L, Yu, Wei-Ping, Sun, Xi-Ming, Gui Zhen Tee, Nicole, Li San Tan, Elisabeth, Barton, Paul, J R, Felkin, Leanne, E, Lara-Pezzi, Enrique, Angelini, Gianni, Beltrami, Cristina, Pravenec, Michal, Schafer, Sebastian, Bottolo, Leonardo, Hubner, Norbert, Emanueli, Costanza, Cook, Stuart, Petretto, Enrico |
| المساهمون: | Cardiovascular and Metabolic Disorders Singapor (cvmd), Duke-NUS Medical School Singapore, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Ospedale San Giovanni di Dio, Firenze, National Heart and Lung Institute London (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS), Faculty of Medicine London, UK, Imperial College London, Agency for science, technology and research Singapore (A*STAR), Institute of Molecular and Cell Biology, National University of Singapore (NUS)-Agency for science, technology and research Singapore (A*STAR), MRC London Institute of Medical Sciences (LMC), National Heart Centre Singapore (NHCS), Royal Brompton and Harefield NHS Foundation Trust, Cardiovascular Research Centre London, Centro Nacional de Investigaciones Cardiovasculares Carlos III Madrid, Spain (CNIC), Instituto de Salud Carlos III Madrid (ISC), University of Bristol Bristol, Institute of Physiology Prague, Czech Academy of Sciences Prague (CAS), University of Cambridge UK (CAM), The Alan Turing Institute, MRC Biostatistics Unit Cambridge, UK, Max Delbrück Center for Molecular Medicine Berlin (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Charité - UniversitätsMedizin = Charité - University Hospital Berlin, The research was primarily supported by National Medical Research Council (NMRC) Singapore grant NMRC/CBRG/0106/2016 (to E.P.) and the British Heart Foundation (BHF) Ph.D. Studentship grant FS/11/25/28740 (to E.P). We acknowledge additional funding support from European Union FP7 CardioNeT-ITN-289600 (to E.L.-P., S.A.C., and P.J.R.B.), Heart Research UK (to P.J.R.B.), NIHR CV BRU of Royal Brompton and Harefield, NHS Foundation Trust (to S.A.C. and P.J.R.B.), BHF (to S.A.C.), Leducq Foundation (to S.A.C.), MRC UK (to S.A.C.), BHF Program Grant no. RG/15/5/31446 (to C.E. and E.P.). M.P. was supported by Praemium Academiae award of the Czech Academy of Sciences and grant 14-36804G from the Czech Science Foundation., We wish to thank Dr. Jacques Behmoaras for contributing critical and constructive comments to the manuscript., European Project: 289600,EC:FP7:PEOPLE,FP7-PEOPLE-2011-ITN,CARDIONET(2012) |
| المصدر: | ISSN: 2041-1723. |
| بيانات النشر: | HAL CCSD Nature Publishing Group |
| سنة النشر: | 2019 |
| المجموعة: | Institut Pasteur: HAL |
| مصطلحات موضوعية: | Ubiquitin ligases, Cardiomyopathies, MESH: Adolescent, MESH: Adult, MESH: Fibrosis / genetics, MESH: Fibrosis / metabolism, MESH: Mice, Transgenic, MESH: Gene Regulatory Networks, MESH: Genetic Predisposition to Disease* / genetics, MESH: Heart Diseases / genetics, MESH: Heart Diseases / metabolism, MESH: Humans, MESH: Male, MESH: Ubiquitin-Protein Ligases / metabolism, MESH: Middle Aged, MESH: Aged, MESH: Protein Isoforms, MESH: Smad2 Protein / genetics, MESH: Smad2 Protein / metabolism, MESH: Transforming Growth Factor beta / metabolism, MESH: Ubiquitin-Protein Ligases / genetics, MESH: Young Adult, MESH: Gene Expression Regulation, MESH: Animals, MESH: Cardiomyopathies / genetics, MESH: Cardiomyopathies / metabolism, MESH: Extracellular Matrix Proteins / metabolism, MESH: Female, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics |
| الوصف: | International audience ; Cardiac fibrosis is a final common pathology in inherited and acquired heart diseases that causes cardiac electrical and pump failure. Here, we use systems genetics to identify a pro-fibrotic gene network in the diseased heart and show that this network is regulated by the E3 ubiquitin ligase WWP2, specifically by the WWP2-N terminal isoform. Importantly, the WWP2-regulated pro-fibrotic gene network is conserved across different cardiac diseases characterized by fibrosis: human and murine dilated cardiomyopathy and repaired tetralogy of Fallot. Transgenic mice lacking the N-terminal region of the WWP2 protein show improved cardiac function and reduced myocardial fibrosis in response to pressure overload or myo-cardial infarction. In primary cardiac fibroblasts, WWP2 positively regulates the expression of pro-fibrotic markers and extracellular matrix genes. TGFβ1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGFβ1-induced nucleocytoplasmic shuttling and tran-scriptional activity of SMAD2. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/31399586; info:eu-repo/grantAgreement/EC/FP7/289600/EU/Translational Training network on the Cellular and Molecular Bases of Heart Homeostasis and Repair/CARDIONET; pasteur-02868982; https://pasteur.hal.science/pasteur-02868982Test; https://pasteur.hal.science/pasteur-02868982/documentTest; https://pasteur.hal.science/pasteur-02868982/file/Chen_Nature%20Communication_2019.pdfTest; PUBMED: 31399586; PUBMEDCENTRAL: PMC6689010 |
| DOI: | 10.1038/s41467-019-11551-9 |
| الإتاحة: | https://doi.org/10.1038/s41467-019-11551-9Test https://pasteur.hal.science/pasteur-02868982Test https://pasteur.hal.science/pasteur-02868982/documentTest https://pasteur.hal.science/pasteur-02868982/file/Chen_Nature%20Communication_2019.pdfTest |
| حقوق: | http://creativecommons.org/licenses/byTest/ ; info:eu-repo/semantics/OpenAccess |
| رقم الانضمام: | edsbas.B99D337C |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41467-019-11551-9 |
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