WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985823%3A_____%2F19%3A00507837" target="_blank" >RIV/67985823:_____/19:00507837 - isvavai.cz</a>

Výsledek na webu

<a href="https://doi.org/10.1038/s41467-019-11551-9" target="_blank" >https://doi.org/10.1038/s41467-019-11551-9</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41467-019-11551-9" target="_blank" >10.1038/s41467-019-11551-9</a>

Jazyk výsledku

angličtina

Název v původním jazyce

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

Popis výsledku v původním jazyce

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. TGF beta 1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGF beta 1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2.

Název v anglickém jazyce

WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

Popis výsledku anglicky

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. TGF beta 1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGF beta 1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30201 - Cardiac and Cardiovascular systems

Projekt

<a href="/cs/project/GB14-36804G" target="_blank" >GB14-36804G: Centrum mitochondriální biologie a patologie (MITOCENTRUM)</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Nature Communications

ISSN

2041-1723

e-ISSN

—

Svazek periodika

10

Číslo periodika v rámci svazku

Aug 9

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

19

Strana od-do

3616

Kód UT WoS článku

000480234600007

EID výsledku v databázi Scopus

2-s2.0-85070403874