Sirt1 regulates canonical TGF-beta signalling to control fibroblast activation and tissue fibrosis

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F16%3A10323224" target="_blank" >RIV/00216208:11110/16:10323224 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00023728:_____/16:N0000080

Výsledek na webu

<a href="http://dx.doi.org/10.1136/annrheumdis-2014-205740" target="_blank" >http://dx.doi.org/10.1136/annrheumdis-2014-205740</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1136/annrheumdis-2014-205740" target="_blank" >10.1136/annrheumdis-2014-205740</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Sirt1 regulates canonical TGF-beta signalling to control fibroblast activation and tissue fibrosis

Popis výsledku v původním jazyce

Background Sirt1 is a member of the sirtuin family of proteins. Sirt1 is a class III histone deacetylase with important regulatory roles in transcription, cellular differentiation, proliferation and metabolism. As aberrant epigenetic modifications have been linked to the pathogenesis of systemic sclerosis (SSc), we aimed to investigate the role of Sirt1 in fibroblast activation. Methods Sirt1 expression was analysed by real-time PCR, western blot and immunohistochemistry. Sirt1 signalling was modulated with the Sirt1 agonist resveratrol and by fibroblast-specific knockout. The role of Sirt1 was evaluated in bleomycin-induced skin fibrosis and in mice overexpressing a constitutively active transforming growth factor-beta (TGF-beta) receptor I (TBRIact). Results The expression of Sirt1 was decreased in patients with SSc and in experimental fibrosis in a TGF-beta-dependent manner. Activation of Sirt1 potentiated the profibrotic effects of TGF-beta with increased Smad reporter activity, elevated transcription of TGF-beta target genes and enhanced release of collagen. In contrast, knockdown of Sirt1 inhibited TGF-beta/SMAD signalling and reduced release of collagen in fibroblasts. Consistently, mice with fibroblast-specific knockdown of Sirt1 were less susceptible to bleomycin-or TBRIact-induced fibrosis. Conclusions We identified Sirt1 as a crucial regulator of TGF-beta/Smad signalling in SSc. Although Sirt1 is downregulated, this decrease is not sufficient to counterbalance the excessive activation of TGF-beta signalling in SSc. However, augmentation of this endogenous regulatory mechanism, for example, by knockdown of Sirt1, can effectively inhibit TGF-beta signalling and exerts potent antifibrotic effects. Sirt1 may thus be a key regulator of fibroblast activation in SSc.

Název v anglickém jazyce

Sirt1 regulates canonical TGF-beta signalling to control fibroblast activation and tissue fibrosis

Popis výsledku anglicky

Background Sirt1 is a member of the sirtuin family of proteins. Sirt1 is a class III histone deacetylase with important regulatory roles in transcription, cellular differentiation, proliferation and metabolism. As aberrant epigenetic modifications have been linked to the pathogenesis of systemic sclerosis (SSc), we aimed to investigate the role of Sirt1 in fibroblast activation. Methods Sirt1 expression was analysed by real-time PCR, western blot and immunohistochemistry. Sirt1 signalling was modulated with the Sirt1 agonist resveratrol and by fibroblast-specific knockout. The role of Sirt1 was evaluated in bleomycin-induced skin fibrosis and in mice overexpressing a constitutively active transforming growth factor-beta (TGF-beta) receptor I (TBRIact). Results The expression of Sirt1 was decreased in patients with SSc and in experimental fibrosis in a TGF-beta-dependent manner. Activation of Sirt1 potentiated the profibrotic effects of TGF-beta with increased Smad reporter activity, elevated transcription of TGF-beta target genes and enhanced release of collagen. In contrast, knockdown of Sirt1 inhibited TGF-beta/SMAD signalling and reduced release of collagen in fibroblasts. Consistently, mice with fibroblast-specific knockdown of Sirt1 were less susceptible to bleomycin-or TBRIact-induced fibrosis. Conclusions We identified Sirt1 as a crucial regulator of TGF-beta/Smad signalling in SSc. Although Sirt1 is downregulated, this decrease is not sufficient to counterbalance the excessive activation of TGF-beta signalling in SSc. However, augmentation of this endogenous regulatory mechanism, for example, by knockdown of Sirt1, can effectively inhibit TGF-beta signalling and exerts potent antifibrotic effects. Sirt1 may thus be a key regulator of fibroblast activation in SSc.

Druh

J_x - Nezařazeno - Článek v odborném periodiku (Jimp, Jsc a Jost)

CEP obor

FE - Ostatní obory vnitřního lékařství

OECD FORD obor

—

Projekt

—

Návaznosti

V - Vyzkumna aktivita podporovana z jinych verejnych zdroju

Rok uplatnění

2016

Kód důvěrnosti údajů

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

Název periodika

Annals of the Rheumatic Diseases

ISSN

0003-4967

e-ISSN

—

Svazek periodika

75

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

8

Strana od-do

226-233

Kód UT WoS článku

000366402400030

EID výsledku v databázi Scopus

2-s2.0-84953886622