An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Publication type
- Published Erratum 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.
- MeSH
- Adult MeSH
- Extracellular Matrix Proteins metabolism MeSH
- Fibrosis genetics metabolism MeSH
- Genetic Predisposition to Disease * genetics MeSH
- Gene Regulatory Networks * MeSH
- Cardiomyopathies genetics metabolism MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Mice, Transgenic MeSH
- Mice MeSH
- Heart Diseases genetics metabolism MeSH
- Protein Isoforms MeSH
- Smad2 Protein genetics metabolism MeSH
- Gene Expression Regulation MeSH
- Aged MeSH
- Transforming Growth Factor beta metabolism MeSH
- Ubiquitin-Protein Ligases genetics metabolism MeSH
- Animals MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Mice MeSH
- Aged MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
