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Journal Articles Nature Communications Year : 2019

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

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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 myo-cardial 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 tran-scriptional activity of SMAD2.
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pasteur-02868982 , version 1 (15-06-2020)

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Attribution - CC BY 4.0

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Huimei Chen, Aida Moreno-Moral, Francesco Pesce, Nithya Devapragash, Massimiliano Mancini, et al.. WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling. Nature Communications, 2019, 10 (1), pp.3616. ⟨10.1038/s41467-019-11551-9⟩. ⟨pasteur-02868982⟩

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