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WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

Huimei Chen 1 Aida Moreno-Moral 1 Francesco Pesce 2 Nithya Devapragash 1 Massimiliano Mancini 3 Ee Ling Heng 4 Maxime Rotival 5 Prashant Srivastava 6 Nathan Harmston 1 Kirill Shkura 6 Owen Rackham 1 Wei-Ping Yu 7, 8 Xi-Ming Sun 9 Nicole Gui Zhen Tee 10 Elisabeth Li San Tan 1 Paul Barton 4, 10 Leanne Felkin 11, 12 Enrique Lara-Pezzi 13 Gianni Angelini 4, 14 Cristina Beltrami 4 Michal Pravenec 15 Sebastian Schafer 1, 10 Leonardo Bottolo 16, 17, 18 Norbert Hubner 19, 20, 21, 22 Costanza Emanueli 4, 12 Stuart Cook 1, 9, 10 Enrico Petretto 9, 1, *
* Corresponding author
1 cvmd - Cardiovascular and Metabolic Disorders [Singapor]
2 UNIBA - University of Bari Aldo Moro
3 Ospedale San Giovanni di Dio, Firenze
4 NHLI - National Heart and Lung Institute [London]
5 Génétique Evolutive Humaine - Human Evolutionary Genetics
6 Faculty of Medicine [London, UK]
7 A*STAR - Agency for science, technology and research [Singapore]
8 Institute of Molecular and Cell Biology
9 LMC - MRC London Institute of Medical Sciences
10 NHCS - National Heart Centre Singapore
11 Royal Brompton and Harefield NHS Foundation Trust
12 Cardiovascular Research Centre [London]
13 CNIC - Centro Nacional de Investigaciones Cardiovasculares Carlos III [Madrid, Spain]
14 University of Bristol [Bristol]
15 Institute of Physiology [Prague]
16 CAM - University of Cambridge [UK]
17 The Alan Turing Institute
18 MRC Biostatistics Unit [Cambridge, UK]
19 MDC - Max Delbrück Center for Molecular Medicine [Berlin]
20 DZHK - German Center for Cardiovascular Research
21 Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin
22 BIH - Berlin Institute of Health
Abstract : 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.
Keywords : Cardiomyopathies Ubiquitin ligases
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Huimei Chen, Aida Moreno-Moral, Francesco Pesce, Nithya Devapragash, Massimiliano Mancini, et al.. WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling. Nature Communications, Nature Publishing Group, 2019, 10 (1), pp.3616. ⟨10.1038/s41467-019-11551-9⟩. ⟨pasteur-02868982⟩

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