WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

H. Chen; A. Moreno-Moral; Francesco Pesce; N. Devapragash; M. Mancini; E. L. Heng; M. Rotival; P. K. Srivastava; N. Harmston; K. Shkura; O. J. L. Rackham; Yu W. -P.; Sun X. -M.; N. G. Z. Tee; E. L. S. Tan; P. J. R. Barton; L. E. Felkin; E. Lara-Pezzi; G. Angelini; C. Beltrami; M. Pravenec; S. Schafer; L. Bottolo; N. Hubner; C. Emanueli; S. A. Cook; E. Petretto

doi:10.1038/s41467-019-11551-9

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

H. Chen
, A. Moreno-Moral
, Francesco Pesce
, N. Devapragash
, M. Mancini
, E. L. Heng
, M. Rotival
, P. K. Srivastava
, N. Harmston
, K. Shkura
, O. J. L. Rackham
, Yu W. -P.
, Sun X. -M.
, N. G. Z. Tee
, E. L. S. Tan
, P. J. R. Barton
, L. E. Felkin
, E. Lara-Pezzi
, G. Angelini
, C. Beltrami

M. Pravenec, S. Schafer, L. Bottolo, N. Hubner, C. Emanueli, S. A. Cook, E. Petretto^*

^*Corresponding author

Duke-National University of Singapore Medical School
Institut Pasteur Paris
Imperial College London
Centro Nacional de Investigaciones Cardiovasculares
Southmead Hospital
Czech Academy of Sciences
National Heart Centre Singapore
University of Cambridge
Alan Turing Institute
Charité – Universitätsmedizin Berlin
German Centre for Cardiovascular Research
Berlin Institute of Health
Max Delbrück Center for Molecular Medicine in the Helmholtz Association
Royal Brompton and Harefield Trust

Research output: Contribution to 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.

Original language	English
Pages (from-to)	1-1
Number of pages	1
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-11551-9
Publication status	Published - 2019

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General
General Physics and Astronomy

Keywords

Fibrosis

Access to Document

10.1038/s41467-019-11551-9

Cite this

Chen, H., Moreno-Moral, A., Pesce, F., Devapragash, N., Mancini, M., Heng, E. L., Rotival, M., Srivastava, P. K., Harmston, N., Shkura, K., Rackham, O. J. L., -P., Y. W., -M., S. X., Tee, N. G. Z., Tan, E. L. S., Barton, P. J. R., Felkin, L. E., Lara-Pezzi, E., Angelini, G., ... Petretto, E. (2019). WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling. Nature Communications, 10(1), 1-1. https://doi.org/10.1038/s41467-019-11551-9

@article{d52ce72067d9483cafb094495e83e437,

title = "WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling",

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.",

keywords = "Fibrosis, Fibrosis",

author = "H. Chen and A. Moreno-Moral and Francesco Pesce and N. Devapragash and M. Mancini and Heng, \{E. L.\} and M. Rotival and Srivastava, \{P. K.\} and N. Harmston and K. Shkura and Rackham, \{O. J. L.\} and -P., \{Yu W.\} and -M., \{Sun X.\} and Tee, \{N. G. Z.\} and Tan, \{E. L. S.\} and Barton, \{P. J. R.\} and Felkin, \{L. E.\} and E. Lara-Pezzi and G. Angelini and C. Beltrami and M. Pravenec and S. Schafer and L. Bottolo and N. Hubner and C. Emanueli and Cook, \{S. A.\} and E. Petretto",

year = "2019",

doi = "10.1038/s41467-019-11551-9",

language = "English",

volume = "10",

pages = "1--1",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Chen, H, Moreno-Moral, A, Pesce, F, Devapragash, N, Mancini, M, Heng, EL, Rotival, M, Srivastava, PK, Harmston, N, Shkura, K, Rackham, OJL, -P., YW, -M., SX, Tee, NGZ, Tan, ELS, Barton, PJR, Felkin, LE, Lara-Pezzi, E, Angelini, G, Beltrami, C, Pravenec, M, Schafer, S, Bottolo, L, Hubner, N, Emanueli, C, Cook, SA & Petretto, E 2019, 'WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling', Nature Communications, vol. 10, no. 1, pp. 1-1. https://doi.org/10.1038/s41467-019-11551-9

TY - JOUR

T1 - WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

AU - Chen, H.

AU - Moreno-Moral, A.

AU - Pesce, Francesco

AU - Devapragash, N.

AU - Mancini, M.

AU - Heng, E. L.

AU - Rotival, M.

AU - Srivastava, P. K.

AU - Harmston, N.

AU - Shkura, K.

AU - Rackham, O. J. L.

AU - -P., Yu W.

AU - -M., Sun X.

AU - Tee, N. G. Z.

AU - Tan, E. L. S.

AU - Barton, P. J. R.

AU - Felkin, L. E.

AU - Lara-Pezzi, E.

AU - Angelini, G.

AU - Beltrami, C.

AU - Pravenec, M.

AU - Schafer, S.

AU - Bottolo, L.

AU - Hubner, N.

AU - Emanueli, C.

AU - Cook, S. A.

AU - Petretto, E.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - Fibrosis

UR - https://publicatt.unicatt.it/handle/10807/332218

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U2 - 10.1038/s41467-019-11551-9

DO - 10.1038/s41467-019-11551-9

M3 - Article

SN - 2041-1723

VL - 10

SP - 1

EP - 1

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

Abstract

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All Science Journal Classification (ASJC) codes

Keywords

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