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WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling
H. Chen, A. Moreno-Moral, F. Pesce, N. Devapragash, M. Mancini, EL. Heng, M. Rotival, PK. Srivastava, N. Harmston, K. Shkura, OJL. Rackham, WP. Yu, XM. Sun, NGZ. Tee, ELS. Tan, PJR. Barton, LE. Felkin, E. Lara-Pezzi, G. Angelini, C. Beltrami, M....
Jazyk angličtina Země Velká Británie
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
MR/M003191/1
Medical Research Council - United Kingdom
SP/10/10/28431
British Heart Foundation - United Kingdom
NLK
Directory of Open Access Journals
od 2015
Free Medical Journals
od 2010
Nature Open Access
od 2010-12-01
PubMed Central
od 2012
Europe PubMed Central
od 2012
ProQuest Central
od 2010-01-01
Open Access Digital Library
od 2015-01-01
Open Access Digital Library
od 2015-01-01
Medline Complete (EBSCOhost)
od 2012-11-01
Health & Medicine (ProQuest)
od 2010-01-01
ROAD: Directory of Open Access Scholarly Resources
od 2010
- MeSH
- dospělí MeSH
- extracelulární matrix - proteiny metabolismus MeSH
- fibróza genetika metabolismus MeSH
- genetická predispozice k nemoci * genetika MeSH
- genové regulační sítě * MeSH
- kardiomyopatie genetika metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- myši transgenní MeSH
- myši MeSH
- nemoci srdce genetika metabolismus MeSH
- protein - isoformy MeSH
- protein Smad2 genetika metabolismus MeSH
- regulace genové exprese MeSH
- senioři MeSH
- transformující růstový faktor beta metabolismus MeSH
- ubikvitinligasy genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- myši MeSH
- senioři MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.
Centro Nacional de Investigaciones Cardiovasculares CNIC 28029 Madrid Spain
Department of Emergency and Organ Transplantation University of Bari 70124 Bari Italy
Division of Brain Sciences Imperial College Faculty of Medicine London W12 0NN UK
Institute of Physiology Czech Academy of Sciences 142 00 Praha 4 Czech Republic
MRC London Institute of Medical Sciences Imperial College London W12 0NN UK
National Heart and Lung Institute Imperial College London London SW7 2AZ UK
National Heart Centre Singapore Singapore 169609 Republic of Singapore
SOC di Anatomia Patologica Ospedale San Giovanni di Dio 50123 Florence Italy
Unit of Human Evolutionary Genetics Institute Pasteur 75015 Paris France
Citace poskytuje Crossref.org
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- $a 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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- $a Yu, Wei-Ping $u Animal Gene Editing Laboratory, BRC, A*STAR20 Biopolis Way, Singapore, 138668, Republic of Singapore. Institute of Molecular and Cell Biology, A*STAR, 61 Biopolis Drive, Singapore, 138673, Republic of Singapore.
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