The NCOA1-CBP-NF-κB transcriptional complex induces inflammation response and triggers endotoxin-induced myocardial dysfunction.
Exp Cell Res
; 415(2): 113114, 2022 06 15.
Article
in En
| MEDLINE
| ID: mdl-35339471
ABSTRACT
Inflammatory pathways represented by TLR4/NF-κB (Toll-like receptor 4/Nuclear factor-κB) axis signaling are activated in the pathogenesis of endotoxin-induced myocardial dysfunction (EIMD). However, the underlying mechanism by which NF-κB coordinates with other transcriptional coactivators/corepressors to regulate the expression of proinflammatory cytokine genes remains unclear. We established an EIMD-mouse model by intraperitoneal injection of lipopolysaccharides (LPS), and we discovered that NCOA1 (nuclear receptor coactivator 1) assembled with CBP (CREB binding protein) and NF-κB subunits to form a transcriptional complex that specifically bound to promoters of proinflammatory cytokine genes to activate their expression. LPS treatment also inhibited DNMT1 (DNA methyltransferase 1) expression, thereby decreasing DNA methylation of a CpG island located on the promoter of NCOA1 and causing NCOA1 overexpression. Screening small molecules that abolished NCOA1-CBP interaction in a yeast system identified a compound PSSM2126 that effectively blocked the NCOA1-CBP interaction in vitro and in vivo. Administration of PSSM2126 to EIMD mice significantly alleviated the inflammation response and improved cardiac function. Collectively, our results reveal that an NCOA1-dependent transactivation mechanism can regulate proinflammatory cytokine expression, thereby improving our understanding of the activation of NF-κB targets. The promising inhibition of the NCOA1-CBP interaction by PSSM2126 may provide a new therapeutic option for EIMD.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
NF-kappa B
/
CREB-Binding Protein
/
Nuclear Receptor Coactivator 1
/
Heart
/
Inflammation
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Exp Cell Res
Year:
2022
Type:
Article
Affiliation country:
China