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 K Srivastava (6) , Nathan Harmston (1) , Kirill Shkura (6) , Owen J L Rackham (1) , Wei-Ping Yu (7, 8) , Xi-Ming Sun (9) , Nicole Gui Zhen Tee (10) , Elisabeth Li San Tan (1) , Paul J R Barton (4, 10) , Leanne E 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)

1 cvmd - Cardiovascular and Metabolic Disorders [Singapor]
2 UNIBA - Università degli studi di Bari Aldo Moro = 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 = Charité - University Hospital [Berlin]
22 BIH - Berlin Institute of Health

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: Ubiquitin ligases; Cardiomyopathies

Domains: Human genetics; Populations and Evolution [q-bio.PE]

Huimei Chen, Aida Moreno-Moral, Francesco Pesce, Nithya Devapragash, Massimiliano Mancini, et al.. WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling. Nature Communications, 2019, 10 (1), pp.3616. ⟨10.1038/s41467-019-11551-9⟩. ⟨pasteur-02868982⟩