Targeting JMJD3 histone demethylase mediates cardiac fibrosis and cardiac function following myocardial infarction.
Biochem Biophys Res Commun
; 528(4): 671-677, 2020 08 06.
Article
em En
| MEDLINE
| ID: mdl-32513540
ABSTRACT
Myocardial fibrosis is the pathological consequence of injury-induced fibroblastto-myofibroblast transition, resulting in increased stiffness and diminished cardiac function. Histone modification has been shown to play an important role in the pathogenesis of cardiac fibrosis. Here, we identified H3K27me3 demethylase JMJD3/KDM6B promotes cardiac fibrosis via regulation of fibrogenic pathways. Using neonatal rat cardiac fibroblasts (NRCF), we show that the expression of endogenous JMJD3 is induced by angiotensin II (Ang II), while the principle extracellular matrix (ECM) such as fibronectin, CTGF, collagen I and III are increased. We find that JMJD3 inhibition markedly enhances the suppressive mark (H3K27me3) at the beta (ß)-catenin promoter in activated cardiac fibroblasts, and then substantially decreases expression of fibrogenic gene. Both inhibition of ß-catenin-mediated transcription with ICG-001 and genetic loss of ß-catenin can prevent Ang II-induced ECM deposition. Most importantly, in vivo inhibition of JMJD3 rescues myocardial ischemia-induced cardiac fibrosis and cardiac dysfunction. Collectively, our findings are the first to report a novel role of histone demethylase JMJD3 in the pro-fibrotic cardiac fibroblast phenotype, pharmacological targeting of JMJD3 might represent a promising therapeutic approach for the treatment of human cardiac fibrosis and other fibrotic diseases.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores Enzimáticos
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Histona Desmetilases com o Domínio Jumonji
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Infarto do Miocárdio
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Miocárdio
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article