WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signalling

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

doi:10.1038/s41467-019-11551-9

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signalling

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

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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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
Article number	3616
Number of pages	19
Journal	Nature Communications
Volume	10
DOIs	https://doi.org/10.1038/s41467-019-11551-9
Publication status	Published - 9 Aug 2019

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Centre for Surgical Research
Water and Environmental Engineering

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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., Yu, W. P., Sun, X. M., 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 signalling. Nature Communications, 10, Article 3616. https://doi.org/10.1038/s41467-019-11551-9

@article{4cc04e7ac34f4d309020075daca18ce9,

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

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.",

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

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Chen, H, Moreno-Moral, A, Pesce, F, Devapragash, N, Mancini, M, Heng, EL, Rotival, M, Srivastava, PK, Harmston, N, Shkura, K, Rackham, OJL, Yu, WP, Sun, XM, 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 signalling', Nature Communications, vol. 10, 3616. https://doi.org/10.1038/s41467-019-11551-9

TY - JOUR

T1 - WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signalling

AU - Chen, Huimei

AU - Moreno-Moral, Aida

AU - Pesce, Francesco

AU - Devapragash, Nithya

AU - Mancini, Massimilano

AU - Heng, Ee Ling

AU - Rotival, Maxime

AU - Srivastava, Prashant K.

AU - Harmston, Nathan

AU - Shkura, Kirill

AU - Rackham, Owen J.L.

AU - Yu, Wei Ping

AU - Sun, Xi Ming

AU - Tee, Nicole Gui Zhen

AU - Tan, Elisabeth Li Sa

AU - Barton, Paul J.R.

AU - Felkin, Leanne E.

AU - Lara-Pezzi, Enrique

AU - Angelini, Gianni

AU - Beltrami, Cristina

AU - Pravenec, Michal

AU - Schafer, Sebastian

AU - Bottolo, Leonardo

AU - Hubner, Norbert

AU - Emanueli, Costanza

AU - Cook, Stuart A

AU - Petretto, Enrico

PY - 2019/8/9

Y1 - 2019/8/9

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.

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U2 - 10.1038/s41467-019-11551-9

DO - 10.1038/s41467-019-11551-9

M3 - Article (Academic Journal)

C2 - 31399586

AN - SCOPUS:85070403874

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

M1 - 3616

ER -

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signalling

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Resubmmission of MicroRNAs in ischaemic heart disease and diabetes mellitus: from cardiac surgery to basic science - and back

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WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signalling

Abstract

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UN SDGs

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Resubmmission of MicroRNAs in ischaemic heart disease and diabetes mellitus: from cardiac surgery to basic science - and back

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