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Activation of ATM/Akt/CREB/eNOS Signaling Axis by Aphidicolin Increases NO Production and Vessel Relaxation in Endothelial Cells and Rat Aortas

Title
Activation of ATM/Akt/CREB/eNOS Signaling Axis by Aphidicolin Increases NO Production and Vessel Relaxation in Endothelial Cells and Rat Aortas
Authors
Park, Jung-HyunCho, Du-HyongHwang, Yun-JinLee, Jee YoungLee, Hyeon-JuJo, Inho
Ewha Authors
조인호이현주이지영
SCOPUS Author ID
조인호scopusscopus; 이현주scopus; 이지영scopusscopus
Issue Date
2020
Journal Title
BIOMOLECULES & THERAPEUTICS
ISSN
1976-9148JCR Link

2005-4483JCR Link
Citation
BIOMOLECULES & THERAPEUTICS vol. 28, no. 6, pp. 549 - 560
Keywords
Endothelial nitric oxide synthaseNitric oxideVessel relaxationAphidicolinDNA damage response
Publisher
KOREAN SOC APPLIED PHARMACOLOGY
Indexed
SCIE; SCOPUS; KCI WOS
Document Type
Article
Abstract
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(133) level, eNOS expression, and NO production. Furthermore, ectopic expression of dominant-negative Akt construct attenuated aphidicolin-stimulated NO production. Aphidicolin increased p-ATM-Ser(1981) and the knockdown of ATM using siRNA attenuated all stimulatory effects of aphidicolin on p-Akt-Ser(473), p-CREB-Ser(133), eNOS expression, and NO production. Additionally, these stimulatory effects of aphidicolin were similarly observed in human umbilical vein endothelial cells. Lastly, aphidicolin increased acetylcholine-induced vessel relaxation in rat aortas, which was accompanied by increased p-ATM-Ser(1981), p-Akt-Ser(473), p-CREB-Ser(133), and eNOS expression. In conclusion, our results demonstrate that in response to aphidicolin, activation of ATM/Akt/CREB/eNOS signaling cascade mediates increase of NO production and vessel relaxation in endothelial cells and rat aortas.
DOI
10.4062/biomolther.2020.007
Appears in Collections:
의과대학 > 의학과 > Journal papers
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