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WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

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Title: WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling
Authors: Chen, H
Moreno-Moral, A
Pesce, F
Devapragash, N
Mancini, M
Heng, E
Rotival, M
Srivastava, P
Harmston, N
Shkura, K
Rackham, O
Yu, W-P
Sun, X-M
Gui Zhen Tee, N
Tan, E
Barton, P
Felkin, L
Lara-Pezzi, E
Angelini, G
Beltrami, C
Pravenec, M
Schafer, S
Bottolo, L
Hubner, N
Emanueli, C
Cook, S
Petretto, E
Item Type: Journal Article
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.
Issue Date: 9-Aug-2019
Date of Acceptance: 19-Jul-2019
URI: http://hdl.handle.net/10044/1/71614
DOI: 10.1038/s41467-019-11551-9
ISSN: 2041-1723
Publisher: Nature Research
Journal / Book Title: Nature Communications
Volume: 10
Issue: 1
Copyright Statement: © The Author(s) 2019. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.
Sponsor/Funder: Fondation Leducq
Commission of the European Communities
Heart Research UK
Fondation Leducq
Fondation Leducq
British Heart Foundation
Medical Research Council (MRC)
British Heart Foundation
Funder's Grant Number: 16CVD03
11 CVD-01
11 CVD-01
Keywords: Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
Publication Status: Published
Article Number: 3616
Appears in Collections:Institute of Clinical Sciences
Faculty of Natural Sciences