WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling.

Autor:	Chen H; Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Republic of Singapore., Moreno-Moral A; Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Republic of Singapore., Pesce F; Department of Emergency and Organ Transplantation (DETO), University of Bari, 70124, Bari, Italy., Devapragash N; Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Republic of Singapore., Mancini M; SOC di Anatomia Patologica, Ospedale San Giovanni di Dio, 50123, Florence, Italy., Heng EL; National Heart and Lung Institute, Imperial College London, London, SW7 2AZ, UK., Rotival M; Unit of Human Evolutionary Genetics, Institute Pasteur, 75015, Paris, France., Srivastava PK; Division of Brain Sciences, Imperial College Faculty of Medicine, London, W12 0NN, UK., Harmston N; Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Republic of Singapore., Shkura K; Division of Brain Sciences, Imperial College Faculty of Medicine, London, W12 0NN, UK., Rackham OJL; Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Republic of Singapore., Yu WP; Animal Gene Editing Laboratory, BRC, A*STAR20 Biopolis Way, Singapore, 138668, Republic of Singapore.; Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Singapore, 138673, Republic of Singapore., Sun XM; MRC London Institute of Medical Sciences (LMC), Imperial College, London, W12 0NN, UK., Tee NGZ; National Heart Centre Singapore, Singapore, 169609, Republic of Singapore., Tan ELS; Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Republic of Singapore., Barton PJR; National Heart and Lung Institute, Imperial College London, London, SW7 2AZ, UK.; Cardiovascular Research Centre, Royal Brompton and Harefield NHS Trust, London, SW3 6NP, UK., Felkin LE; National Heart and Lung Institute, Imperial College London, London, SW7 2AZ, UK.; Cardiovascular Research Centre, Royal Brompton and Harefield NHS Trust, London, SW3 6NP, UK., Lara-Pezzi E; Centro Nacional de Investigaciones Cardiovasculares - CNIC, 28029, Madrid, Spain., Angelini G; National Heart and Lung Institute, Imperial College London, London, SW7 2AZ, UK.; Bristol Heart Institute, Bristol Medical School, University of Bristol, Bristol, BS2 89HW, UK., Beltrami C; National Heart and Lung Institute, Imperial College London, London, SW7 2AZ, UK., Pravenec M; Institute of Physiology, Czech Academy of Sciences, 142 00, Praha 4, Czech Republic., Schafer S; Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Republic of Singapore.; National Heart Centre Singapore, Singapore, 169609, Republic of Singapore., Bottolo L; Department of Medical Genetics, University of Cambridge, Cambridge, CB2 0QQ, UK.; The Alan Turing Institute, London, NW1 2DB, UK.; MRC Biostatistics Unit, University of Cambridge, Cambridge, CB2 0SR, UK., Hubner N; Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125, Berlin, Germany.; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 13347, Berlin, Germany.; Charité-Universitätsmedizin, 10117, Berlin, Germany.; Berlin Institute of Health (BIH), 10178, Berlin, Germany., Emanueli C; National Heart and Lung Institute, Imperial College London, London, SW7 2AZ, UK.; Cardiovascular Research Centre, Royal Brompton and Harefield NHS Trust, London, SW3 6NP, UK., Cook SA; Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Republic of Singapore.; MRC London Institute of Medical Sciences (LMC), Imperial College, London, W12 0NN, UK.; National Heart Centre Singapore, Singapore, 169609, Republic of Singapore., Petretto E; Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore, 169857, Republic of Singapore. enrico.petretto@duke-nus.edu.sg.; MRC London Institute of Medical Sciences (LMC), Imperial College, London, W12 0NN, UK. enrico.petretto@duke-nus.edu.sg.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2019 Aug 09; Vol. 10 (1), pp. 3616. Date of Electronic Publication: 2019 Aug 09.
DOI:	10.1038/s41467-019-11551-9
Abstrakt:	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.
Databáze:	MEDLINE
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