The University of Southampton
×
Filter your search:
University of Southampton Institutional Repository

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling
WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

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.

Adolescent, Adult, Aged, Animals, Cardiomyopathies/genetics, Extracellular Matrix Proteins/metabolism, Female, Fibrosis/genetics, Gene Expression Regulation, Gene Regulatory Networks, Genetic Predisposition to Disease/genetics, Heart Diseases/genetics, Humans, Male, Mice, Mice, Transgenic, Middle Aged, Protein Isoforms, Smad2 Protein/genetics, Transforming Growth Factor beta/metabolism, Ubiquitin-Protein Ligases/genetics, Young Adult
2041-1723
3616
Chen, Huimei
c2d53f26-c0f2-4012-9c74-b4977a6731c5
Moreno-Moral, Aida
7b93f81e-5505-4c2e-bc8f-916daa5d2546
Pesce, Francesco
467bbdb1-0bfa-4f95-a5cd-47b3bedfe064
Devapragash, Nithya
65582ef3-3854-43b7-bfff-f59950ba50b0
Mancini, Massimiliano
5718ba9a-577d-4f2e-a367-912fa730dd23
Heng, Ee Ling
8306bcd8-93ef-42dc-b59d-a86b03116b21
Rotival, Maxime
5d5e41da-6a7d-4ed7-bafe-fda53d5cd4f5
Srivastava, Prashant K
be70bb08-c734-40bb-8b98-32c00bf42c2c
Harmston, Nathan
017e019d-7784-4ed4-a4d9-38880f08df3f
Shkura, Kirill
68193e9b-7c17-4526-a970-2750c95b44d2
Rackham, Owen J L
8122eb1f-6e9f-4da5-90e1-ce108ccbbcbf
Yu, Wei-Ping
7368567b-a400-42a1-bd43-6114292ce8b1
Sun, Xi-Ming
6cbc2fd3-70e9-46c4-b736-d02325a3051d
Tee, Nicole Gui Zhen
deed81b1-999d-4c90-b283-73f5331ec200
Tan, Elisabeth Li Sa
cd326a7d-7548-495d-9a43-afc7584782a2
Barton, Paul J R
240f673f-f2f1-466b-9f95-6410b41230f4
Felkin, Leanne E
5324f950-1234-4c33-85d2-6d7be8555ee3
Lara-Pezzi, Enrique
6bd067e8-225c-4f00-a24e-f2900a422d7f
Angelini, Gianni
36437e97-0cf6-4385-af7e-c583d89c782d
Beltrami, Cristina
3b0ff064-0dce-41cd-b3e1-11b9592afa6b
Pravenec, Michal
8a52c55c-7d83-4a2f-8528-7bebcb864ef0
Schafer, Sebastian
6946786d-17c8-4c35-a6ac-871cc7a82cf2
Bottolo, Leonardo
12a7f8db-e00a-42fd-b8f8-01763add4fb9
Hubner, Norbert
e01e1d75-f475-4d26-a3de-ba4150133c34
Emanueli, Costanza
1588631a-fd2b-4735-9a0c-5f68bbd66c19
Cook, Stuart A
2c9730f9-0c9b-4d81-a32b-2fa1180b8153
Petretto, Enrico
a8a7d254-ea06-4ab3-ba7e-b653349a29f4
Chen, Huimei
c2d53f26-c0f2-4012-9c74-b4977a6731c5
Moreno-Moral, Aida
7b93f81e-5505-4c2e-bc8f-916daa5d2546
Pesce, Francesco
467bbdb1-0bfa-4f95-a5cd-47b3bedfe064
Devapragash, Nithya
65582ef3-3854-43b7-bfff-f59950ba50b0
Mancini, Massimiliano
5718ba9a-577d-4f2e-a367-912fa730dd23
Heng, Ee Ling
8306bcd8-93ef-42dc-b59d-a86b03116b21
Rotival, Maxime
5d5e41da-6a7d-4ed7-bafe-fda53d5cd4f5
Srivastava, Prashant K
be70bb08-c734-40bb-8b98-32c00bf42c2c
Harmston, Nathan
017e019d-7784-4ed4-a4d9-38880f08df3f
Shkura, Kirill
68193e9b-7c17-4526-a970-2750c95b44d2
Rackham, Owen J L
8122eb1f-6e9f-4da5-90e1-ce108ccbbcbf
Yu, Wei-Ping
7368567b-a400-42a1-bd43-6114292ce8b1
Sun, Xi-Ming
6cbc2fd3-70e9-46c4-b736-d02325a3051d
Tee, Nicole Gui Zhen
deed81b1-999d-4c90-b283-73f5331ec200
Tan, Elisabeth Li Sa
cd326a7d-7548-495d-9a43-afc7584782a2
Barton, Paul J R
240f673f-f2f1-466b-9f95-6410b41230f4
Felkin, Leanne E
5324f950-1234-4c33-85d2-6d7be8555ee3
Lara-Pezzi, Enrique
6bd067e8-225c-4f00-a24e-f2900a422d7f
Angelini, Gianni
36437e97-0cf6-4385-af7e-c583d89c782d
Beltrami, Cristina
3b0ff064-0dce-41cd-b3e1-11b9592afa6b
Pravenec, Michal
8a52c55c-7d83-4a2f-8528-7bebcb864ef0
Schafer, Sebastian
6946786d-17c8-4c35-a6ac-871cc7a82cf2
Bottolo, Leonardo
12a7f8db-e00a-42fd-b8f8-01763add4fb9
Hubner, Norbert
e01e1d75-f475-4d26-a3de-ba4150133c34
Emanueli, Costanza
1588631a-fd2b-4735-9a0c-5f68bbd66c19
Cook, Stuart A
2c9730f9-0c9b-4d81-a32b-2fa1180b8153
Petretto, Enrico
a8a7d254-ea06-4ab3-ba7e-b653349a29f4

Chen, Huimei, Moreno-Moral, Aida, Pesce, Francesco, Devapragash, Nithya, Mancini, Massimiliano, Heng, Ee Ling, Rotival, Maxime, Srivastava, Prashant K, Harmston, Nathan, Shkura, Kirill, Rackham, Owen J L, Yu, Wei-Ping, Sun, Xi-Ming, Tee, Nicole Gui Zhen, Tan, Elisabeth Li Sa, Barton, Paul J R, Felkin, Leanne E, Lara-Pezzi, Enrique, Angelini, Gianni, Beltrami, Cristina, Pravenec, Michal, Schafer, Sebastian, Bottolo, Leonardo, Hubner, Norbert, Emanueli, Costanza, Cook, Stuart A and Petretto, Enrico (2019) WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling. Nature Communications, 10 (1), 3616. (doi:10.1038/s41467-019-11551-9).

Record type: 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.

Text
s41467-019-11551-9 - Version of Record
Available under License Creative Commons Attribution.
Download (4MB)

More information

Published date: 9 August 2019
Keywords: Adolescent, Adult, Aged, Animals, Cardiomyopathies/genetics, Extracellular Matrix Proteins/metabolism, Female, Fibrosis/genetics, Gene Expression Regulation, Gene Regulatory Networks, Genetic Predisposition to Disease/genetics, Heart Diseases/genetics, Humans, Male, Mice, Mice, Transgenic, Middle Aged, Protein Isoforms, Smad2 Protein/genetics, Transforming Growth Factor beta/metabolism, Ubiquitin-Protein Ligases/genetics, Young Adult

Identifiers

Local EPrints ID: 455454
URI: http://eprints.soton.ac.uk/id/eprint/455454
DOI: doi:10.1038/s41467-019-11551-9
ISSN: 2041-1723
PURE UUID: d05bc688-dde2-4403-880e-f39fb4eb3596
ORCID for Owen J L Rackham: ORCID iD orcid.org/0000-0002-4390-0872

Catalogue record

Date deposited: 22 Mar 2022 17:37
Last modified: 17 Mar 2024 04:03

Export record

Altmetrics

Contributors

Author: Huimei Chen
Author: Aida Moreno-Moral
Author: Francesco Pesce
Author: Nithya Devapragash
Author: Massimiliano Mancini
Author: Ee Ling Heng
Author: Maxime Rotival
Author: Prashant K Srivastava
Author: Nathan Harmston
Author: Kirill Shkura
Author: Owen J L Rackham ORCID iD
Author: Wei-Ping Yu
Author: Xi-Ming Sun
Author: Nicole Gui Zhen Tee
Author: Elisabeth Li Sa Tan
Author: Paul J R Barton
Author: Leanne E Felkin
Author: Enrique Lara-Pezzi
Author: Gianni Angelini
Author: Cristina Beltrami
Author: Michal Pravenec
Author: Sebastian Schafer
Author: Leonardo Bottolo
Author: Norbert Hubner
Author: Costanza Emanueli
Author: Stuart A Cook
Author: Enrico Petretto

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Library staff additional information
Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×