2026-06-14T03:28:54Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/83342024-10-31T11:56:23Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud
author
Chen, Huimei
author
Moreno-Moral, Aida
author
Pesce, Francesco
author
Devapragash, Nithya
author
Mancini, Massimiliano
author
Heng, Ee Ling
author
Rotival, Maxime
author
Srivastava, Prashant K
author
Harmston, Nathan
author
Shkura, Kirill
author
Rackham, Owen J L
author
Yu, Wei-Ping
author
Sun, Xi-Ming
author
Tee, Nicole Gui Zhen
author
Tan, Elisabeth Li Sa
author
Barton, Paul J R
author
Felkin, Leanne E
author
Lara-Pezzi, Enrique
author
Angelini, Gianni
author
Beltrami, Cristina
author
Pravenec, Michal
author
Schafer, Sebastian
author
Bottolo, Leonardo
author
Hubner, Norbert
author
Emanueli, Costanza
author
Cook, Stuart A
author
Petretto, Enrico
funder
National Medical Research Council (Singapur)
funder
British Heart Foundation
funder
Unión Europea. Comisión Europea
funder
National Institutes of Health (Estados Unidos)
funder
Czech Science Foundation
funder
Fondation Leducq
funder
NHS - Foundation Trust
2019-09-11T07:58:27Z
2019-09-11T07:58:27Z
2019-08
Nat Commun. 2019; 10(1):3616
10.1038/s41467-019-11551-9
2041-1723
2041-1723
Nature communications
31399586
http://hdl.handle.net/20.500.12105/8334
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.
eng
WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling
journal article
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