WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

Huimei Chen, Aida Moreno-Moral, Francesco Pesce, Nithya Devapragash, Massimiliano 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 Beltrami, Michal Pravenec, Sebastian Schafer, Leonardo Bottolo, Norbert Hubner, Costanza Emanueli, Stuart A. Cook and Enrico Petretto ()
Additional contact information
Huimei Chen: Duke-NUS Medical School
Aida Moreno-Moral: Duke-NUS Medical School
Francesco Pesce: University of Bari
Nithya Devapragash: Duke-NUS Medical School
Massimiliano Mancini: Ospedale San Giovanni di Dio
Ee Ling Heng: Imperial College London
Maxime Rotival: Institute Pasteur
Prashant K. Srivastava: Imperial College Faculty of Medicine
Nathan Harmston: Duke-NUS Medical School
Kirill Shkura: Imperial College Faculty of Medicine
Owen J. L. Rackham: Duke-NUS Medical School
Wei-Ping Yu: BRC
Xi-Ming Sun: Imperial College
Nicole Gui Zhen Tee: National Heart Centre Singapore
Elisabeth Li Sa Tan: Duke-NUS Medical School
Paul J. R. Barton: Imperial College London
Leanne E. Felkin: Imperial College London
Enrique Lara-Pezzi: Centro Nacional de Investigaciones Cardiovasculares – CNIC
Gianni Angelini: Imperial College London
Cristina Beltrami: Imperial College London
Michal Pravenec: Czech Academy of Sciences
Sebastian Schafer: Duke-NUS Medical School
Leonardo Bottolo: University of Cambridge
Norbert Hubner: Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC)
Costanza Emanueli: Imperial College London
Stuart A. Cook: Duke-NUS Medical School
Enrico Petretto: Duke-NUS Medical School

Nature Communications, 2019, vol. 10, issue 1, 1-19

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11551-9

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