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. TGF beta 1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGF beta 1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2.

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling / 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.; Beltrami, C.; Pravenec, M.; Schafer, S.; Bottolo, L.; Hubner, N.; Emanueli, C.; Cook, S. A.; Petretto, E.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 10:1(2019), p. 3616. [10.1038/s41467-019-11551-9]

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

Mancini, M.;
2019

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. TGF beta 1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGF beta 1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2.
2019
Adolescent; Adult; Aged; Animals; Cardiomyopathies; Extracellular Matrix Proteins; Female; Fibrosis; Gene Expression Regulation; Heart Diseases; Humans; Male; Mice; Mice, Transgenic; Middle Aged; Protein Isoforms; Smad2 Protein; Transforming Growth Factor beta; Ubiquitin-Protein Ligases; Young Adult; Gene Regulatory Networks; Genetic Predisposition to Disease
01 Pubblicazione su rivista::01a Articolo in rivista
WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling / 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.; Beltrami, C.; Pravenec, M.; Schafer, S.; Bottolo, L.; Hubner, N.; Emanueli, C.; Cook, S. A.; Petretto, E.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 10:1(2019), p. 3616. [10.1038/s41467-019-11551-9]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1654554
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