WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

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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

Edité par CCSD ; Nature Publishing Group -

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.

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