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.

Animal Gene Editing Laboratory BRC A*STAR20 Biopolis Way Singapore 138668 Republic of Singapore

Berlin Institute of Health 10178 Berlin Germany

Bristol Heart Institute Bristol Medical School University of Bristol Bristol BS2 89HW UK

Cardiovascular and Metabolic Sciences Max Delbrück Center for Molecular Medicine in the Helmholtz Association 13125 Berlin Germany

Cardiovascular Research Centre Royal Brompton and Harefield NHS Trust London SW3 6NP UK

Centro Nacional de Investigaciones Cardiovasculares CNIC 28029 Madrid Spain

Charité Universitätsmedizin 10117 Berlin Germany

Department of Emergency and Organ Transplantation University of Bari 70124 Bari Italy

Department of Medical Genetics University of Cambridge Cambridge CB2 0QQ UK

Division of Brain Sciences Imperial College Faculty of Medicine London W12 0NN UK

DZHK Partner Site Berlin 13347 Berlin Germany

Institute of Molecular and Cell Biology A*STAR 61 Biopolis Drive Singapore 138673 Republic of Singapore

Institute of Physiology Czech Academy of Sciences 142 00 Praha 4 Czech Republic

MRC Biostatistics Unit University of Cambridge Cambridge CB2 0SR UK

MRC London Institute of Medical Sciences Imperial College London W12 0NN UK

National Heart and Lung Institute Imperial College London London SW7 2AZ UK

National Heart Centre Singapore Singapore 169609 Republic of Singapore

Programme in Cardiovascular and Metabolic Disorders Duke NUS Medical School Singapore 169857 Republic of Singapore

SOC di Anatomia Patologica Ospedale San Giovanni di Dio 50123 Florence Italy

The Alan Turing Institute London NW1 2DB UK

Unit of Human Evolutionary Genetics Institute Pasteur 75015 Paris France

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Nat Commun. 2019 Sep 9;10(1):4085. doi: 10.1038/s41467-019-12060-5. PubMed

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