Journal Article

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

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

2019

Overview

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. Pathological cardiac fibrosis is a hallmark of diseases leading to heart failure. Here, the authors used systems genetics to identify a pro-fibrotic gene network regulated by WWP2, a E3 ubiquitin ligase, which orchestrates the nucleocytoplasmic shuttling and transcriptional activity of SMAD2 in the diseased heart.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/51 / 13/89 / 14/32 / 14/35 / 38/39 / 42/44 / 45/43 / 631/45/474/2073 / 64/60 / 692/4019/592/75/74 / 82/80 / Adolescent / Adult / Aged / Animals / Cardiomyopathies - genetics / Cardiomyopathies - metabolism / Cardiomyopathy / Cardiovascular disease / Cardiovascular diseases / Coronary artery disease / Dilated cardiomyopathy / Extracellular matrix / Extracellular Matrix Proteins - metabolism / Female / Fibroblasts / Fibrosis / Fibrosis - genetics / Fibrosis - metabolism / Gene expression / Gene Expression Regulation / Gene Regulatory Networks / Genetic Predisposition to Disease - genetics / Genetics / Growth factors / Heart / Heart diseases / Heart Diseases - genetics / Heart Diseases - metabolism / Human genetics / Humanities and Social Sciences / Humans / Isoforms / Life Sciences / Male / Metabolism / Mice / Mice, Transgenic / Middle Aged / multidisciplinary / Myocardial infarction / Nuclear transport / Populations and Evolution / Protein Isoforms / Proteins / Science / Science (multidisciplinary) / Signal transduction / Smad2 protein / Smad2 Protein - genetics / Smad2 Protein - metabolism / Tetralogy of Fallot / Transcription / Transforming Growth Factor beta - metabolism / Transforming growth factor-b1 / Transgenic mice / Translocation / Ubiquitin / Ubiquitin-protein ligase / Ubiquitin-Protein Ligases - genetics / Ubiquitin-Protein Ligases - metabolism / Young Adult