2026-06-14T06:44:38Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/83342024-10-31T11:56:23Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Chen, Huimei author Moreno-Moral, Aida author Pesce, Francesco author Devapragash, Nithya author Mancini, Massimiliano author Heng, Ee Ling author Rotival, Maxime author Srivastava, Prashant K author Harmston, Nathan author Shkura, Kirill author Rackham, Owen J L author Yu, Wei-Ping author Sun, Xi-Ming author Tee, Nicole Gui Zhen author Tan, Elisabeth Li Sa author Barton, Paul J R author Felkin, Leanne E author Lara-Pezzi, Enrique author Angelini, Gianni author Beltrami, Cristina author Pravenec, Michal author Schafer, Sebastian author Bottolo, Leonardo author Hubner, Norbert author Emanueli, Costanza author Cook, Stuart A author Petretto, Enrico author 2019-08 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. Nat Commun. 2019; 10(1):3616 10.1038/s41467-019-11551-9 2041-1723 2041-1723 Nature communications 31399586 http://hdl.handle.net/20.500.12105/8334 WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling