Activation of ATM/Akt/CREB/eNOS Signaling Axis by Aphidicolin Increases NO Production and Vessel Relaxation in Endothelial Cells and Rat Aortas.
Aphidicolin
DNA damage response
Endothelial nitric oxide synthase
Nitric oxide
Vessel relaxation
Journal
Biomolecules & therapeutics
ISSN: 1976-9148
Titre abrégé: Biomol Ther (Seoul)
Pays: Korea (South)
ID NLM: 101472832
Informations de publication
Date de publication:
01 Nov 2020
01 Nov 2020
Historique:
received:
16
01
2020
revised:
26
03
2020
accepted:
06
04
2020
pubmed:
13
5
2020
medline:
13
5
2020
entrez:
13
5
2020
Statut:
ppublish
Résumé
Although DNA damage responses (DDRs) are reported to be involved in nitric oxide (NO) production in response to genotoxic stresses, the precise mechanism of DDR-mediated NO production has not been fully understood. Using a genotoxic agent aphidicolin, we investigated how DDRs regulate NO production in bovine aortic endothelial cells. Prolonged (over 24 h) treatment with aphidicolin increased NO production and endothelial NO synthase (eNOS) protein expression, which was accompanied by increased eNOS dimer/monomer ratio, tetrahydrobiopterin levels, and eNOS mRNA expression. A promoter assay using 5'-serially deleted eNOS promoters revealed that Tax-responsive element site, located at -962 to -873 of the eNOS promoter, was responsible for aphidicolin-stimulated eNOS gene expression. Aphidicolin increased CREB activity and ectopic expression of dominantnegative inhibitor of CREB, A-CREB, repressed the stimulatory effects of aphidicolin on eNOS gene expression and its promoter activity. Co-treatment with LY294002 decreased the aphidicolin-stimulated increase in p-CREB-Ser
Identifiants
pubmed: 32394671
pii: biomolther.2020.007
doi: 10.4062/biomolther.2020.007
pmc: PMC7585642
doi:
Types de publication
Journal Article
Langues
eng
Pagination
549-560Références
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