WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling
| العنوان: | WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling |
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| المؤلفون: | Cristina Beltrami, Owen J. L. Rackham, Costanza Emanueli, Nithya Devapragash, Wei-Ping Yu, Xi-Ming Sun, Stuart A. Cook, Norbert Hubner, Francesco Pesce, Ee Ling Heng, Elisabeth Tan, Aida Moreno-Moral, Enrique Lara-Pezzi, Gianni D Angelini, Enrico Petretto, Huimei Chen, Paul J.R. Barton, Nathan Harmston, Michal Pravenec, Sebastian Schafer, Maxime Rotival, Nicole Tee, Massimilano Mancini, Leanne E. Felkin, Leonardo Bottolo, Prashant K. Srivastava, Kirill Shkura |
| 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), Moreno-Moral, Aida [0000-0002-8155-3146], Barton, Paul J. R. [0000-0002-1165-7767], Schafer, Sebastian [0000-0002-6909-8275], Bottolo, Leonardo [0000-0002-6381-2327], Cook, Stuart A. [0000-0001-6628-194X], Petretto, Enrico [0000-0003-2163-5921], Apollo - University of Cambridge Repository, National Medical Research Council (Singapur), British Heart Foundation, Unión Europea. Comisión Europea, National Institutes of Health (Estados Unidos), Czech Science Foundation, Fondation Leducq, NHS Foundation Trusth, University of Bari Aldo Moro (UNIBA), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Leducq Foundation for Cardiovascular Research, Commission of the European Communities, Heart Research UK, Medical Research Council (MRC), Barton, Paul JR [0000-0002-1165-7767], Cook, Stuart A [0000-0001-6628-194X] |
| المصدر: | Nature Communications Nature Communications, 2019, 10 (1), pp.3616. ⟨10.1038/s41467-019-11551-9⟩ Nature Communications, Vol 10, Iss 1, Pp 1-19 (2019) Chen, H, Moreno-Moral, A, Pesce, F, Devapragash, N, Mancini, M, Heng, E L, Rotival, M, Srivastava, P K, Harmston, N, Shkura, K, Rackham, O J L, Yu, W P, Sun, X M, Tee, N G Z, Tan, E L S, Barton, P J R, Felkin, L E, Lara-Pezzi, E, Angelini, G, Beltrami, C, Pravenec, M, Schafer, S, Bottolo, L, Hubner, N, Emanueli, C, Cook, S A & Petretto, E 2019, ' WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signalling ', Nature Communications, vol. 10, 3616 . https://doi.org/10.1038/s41467-019-11551-9Test Nature Communications, Nature Publishing Group, 2019, 10 (1), pp.3616. ⟨10.1038/s41467-019-11551-9⟩ Repisalud Instituto de Salud Carlos III (ISCIII) |
| بيانات النشر: | Springer Science and Business Media LLC, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Male, 45/43, BLOOD-PRESSURE, 02 engineering and technology, MESH: Protein Isoforms, MESH: Heart Diseases / genetics, Mice, Transforming Growth Factor beta, 42/44, Fibrosis, Protein Isoforms, Medicine, MESH: Animals, lcsh:Science, MESH: Ubiquitin-Protein Ligases / genetics, MESH: Fibrosis / metabolism, MESH: Genetic Predisposition to Disease* / genetics, GENE-EXPRESSION, Regulation of gene expression, Extracellular Matrix Proteins, MESH: Middle Aged, MESH: Fibrosis / genetics, TGF-BETA, MESH: Heart Diseases / metabolism, MESH: Ubiquitin-Protein Ligases / metabolism, 3. Good health, Cell biology, Ubiquitin ligase, FIBROBLAST, MESH: Young Adult, Science & Technology - Other Topics, 64/60, Cardiomyopathies, 0210 nano-technology, Cardiac function curve, Science, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, REVEALS, Humans, Aged, MESH: Adolescent, Science & Technology, MESH: Humans, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], IDENTIFICATION, MESH: Smad2 Protein / metabolism, MESH: Extracellular Matrix Proteins / metabolism, MESH: Adult, MESH: Cardiomyopathies / metabolism, medicine.disease, 030104 developmental biology, Cardiovascular and Metabolic Diseases, E3 UBIQUITIN LIGASE, RAT, DETERMINANT, lcsh:Q, Myocardial fibrosis, MESH: Female, 0301 basic medicine, Cardiac fibrosis, General Physics and Astronomy, Smad2 Protein, Gene Regulatory Networks, 13/89, MESH: Aged, MESH: Transforming Growth Factor beta / metabolism, Multidisciplinary, biology, MESH: Smad2 Protein / genetics, article, Middle Aged, MESH: Cardiomyopathies / genetics, 021001 nanoscience & nanotechnology, 692/4019/592/75/74, MESH: Gene Expression Regulation, Multidisciplinary Sciences, Centre for Surgical Research, HEART-FAILURE, Female, 38/39, Adult, Adolescent, Heart Diseases, MESH: Mice, Transgenic, Ubiquitin-Protein Ligases, Mice, Transgenic, 14/32, 82/80, Young Adult, Animals, Genetic Predisposition to Disease, 14/35, MESH: Mice, Pressure overload, business.industry, General Chemistry, MESH: Male, Gene Expression Regulation, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Ubiquitin ligases, Heart failure, 13/51, biology.protein, 631/45/474/2073, MESH: Gene Regulatory Networks, business |
| الوصف: | 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 myocardial 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 transcriptional activity of SMAD2. Pathological cardiac fibrosis is a hallmark of diseases leading to heart failure. Here, the authors used systems genetics to identify a pro-fibrotic gene network regulated by WWP2, a E3 ubiquitin ligase, which orchestrates the nucleocytoplasmic shuttling and transcriptional activity of SMAD2 in the diseased heart. |
| وصف الملف: | application/pdf; text; application/zip; text/xml |
| تدمد: | 2041-1723 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9b9a8eae768aaa77cac0482318b75243Test https://doi.org/10.1038/s41467-019-11551-9Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....9b9a8eae768aaa77cac0482318b75243 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20411723 |
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