WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signalling

Huimei Chen, Aida Moreno-Moral, Francesco Pesce, Nithya Devapragash, Massimilano Mancini, Ee Ling Heng, Maxime Rotival, Prashant K. Srivastava, Nathan Harmston, Kirill Shkura, Owen J.L. Rackham, Wei Ping Yu, Xi Ming Sun, Nicole Gui Zhen Tee, Elisabeth Li Sa Tan, Paul J.R. Barton, Leanne E. Felkin, Enrique Lara-Pezzi, Gianni Angelini, Cristina BeltramiMichal Pravenec, Sebastian Schafer, Leonardo Bottolo, Norbert Hubner, Costanza Emanueli, Stuart A Cook, Enrico Petretto*

*Corresponding author for this work

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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 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.
Original languageEnglish
Article number3616 (2019)
Number of pages19
JournalNature Communications
Volume10
DOIs
Publication statusPublished - 9 Sep 2019

Structured keywords

  • Centre for Surgical Research

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    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., ... Petretto, E. (2019). WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signalling. Nature Communications, 10, [3616 (2019) ]. https://doi.org/10.1038/s41467-019-11551-9