Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK–eNOS–NO pathway

Endothelial adenosine monophosphate-activated protein kinase (AMPK) plays a critical role in the regulation of vascular tone through stimulating nitric oxide (NO) release in endothelial cells. Since obesity leads to endothelial dysfunction and AMPK dysregulation, AMPK activation might be an importan...

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Autores: Sanz‑Gómez, Marta, Aledavood, Elnaz, Beroiz‑Salaverri, Marina, Lagartera, Laura, Vega‑Martín, Elena, Gil‑Ortega, Marta, Cumella, Jose, Pérez, Concepción, Luque, F. Javier, Estarellas, Carolina, Fernández-Alfonso, María Soledad, Castro Morera, Ana
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2022
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositório:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/269579
Acesso em linha:http://hdl.handle.net/10261/269579
Access Level:Acceso aberto
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spelling Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK–eNOS–NO pathwaySanz‑Gómez, MartaAledavood, ElnazBeroiz‑Salaverri, MarinaLagartera, LauraVega‑Martín, ElenaGil‑Ortega, MartaCumella, JosePérez, ConcepciónLuque, F. JavierEstarellas, CarolinaFernández-Alfonso, María SoledadCastro Morera, AnaEndothelial adenosine monophosphate-activated protein kinase (AMPK) plays a critical role in the regulation of vascular tone through stimulating nitric oxide (NO) release in endothelial cells. Since obesity leads to endothelial dysfunction and AMPK dysregulation, AMPK activation might be an important strategy to restore vascular function in cardiometabolic alterations. Here, we report the identification of a novel AMPK modulator, the indolic derivative IND6, which shows affinity for AMPKα1β1γ1, the primary AMPK isoform in human EA.Hy926 endothelial cells. IND6 shows inhibitory action of the enzymatic activity in vitro, but increases the levels of p-Thr174AMPK, p-Ser1177eNOS and p-Ser79ACC in EA.Hy926. This paradoxical finding might be explained by the ability of IND6 to act as a mixed-type inhibitor, but also to promote the enzyme activation by adopting two distinct binding modes at the ADaM site. Moreover, functional assays reveal that IND6 increased the eNOS-dependent production of NO and elicited a concentration-dependent vasodilation of endothelium-intact rat aorta due to AMPK and eNOS activation, demonstrating a functional activation of the AMPK–eNOS–NO endothelial pathway. This kinase inhibition profile, combined with the paradoxical AMPK activation in cells and arteries, suggests that these new chemical entities may constitute a valuable starting point for the development of new AMPK modulators with therapeutic potential for the treatment of vascular complications associated with obesity.his research was funded by Fundación Eugenio Rodríguez Pascual, the Spanish Ministerio de Economía y Competitividad (MDM-2017-0767), the Spanish Ministerio de Ciencia Innovación y Universidades (RTI2018- 095544-B-I00) and the Generalitat de Catalunya (2017SGR1746) for financial support. Computational resources from the Barcelona Supercomputing Center (BSC; BCV-2019-1-0009 and BCV-2019-2-0017) and the Consorci de Serveis Universitaris de Catalunya (CSUC; Molecular Recognition project) are acknowledged. E.A. thanks AGAUR (Generalitat of Catalunya; 2019FI_B2_00001) for her fellowship. M.S.G. thanks Universidad Com- plutense de Madrid for her fellowship.Peer reviewedSpringer NatureFundación Eugenio Rodríguez PascualMinisterio de Ciencia, Innovación y Universidades (España)Ministerio de Economía y Competitividad (España)Generalitat de CatalunyaUniversidad Complutense de MadridConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202220222022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/269579reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-095544-B-I00https://doi.org/10.1038/s41598-022-07077-8Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2695792026-05-22T06:33:51Z
dc.title.none.fl_str_mv Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK–eNOS–NO pathway
title Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK–eNOS–NO pathway
spellingShingle Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK–eNOS–NO pathway
Sanz‑Gómez, Marta
title_short Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK–eNOS–NO pathway
title_full Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK–eNOS–NO pathway
title_fullStr Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK–eNOS–NO pathway
title_full_unstemmed Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK–eNOS–NO pathway
title_sort Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK–eNOS–NO pathway
dc.creator.none.fl_str_mv Sanz‑Gómez, Marta
Aledavood, Elnaz
Beroiz‑Salaverri, Marina
Lagartera, Laura
Vega‑Martín, Elena
Gil‑Ortega, Marta
Cumella, Jose
Pérez, Concepción
Luque, F. Javier
Estarellas, Carolina
Fernández-Alfonso, María Soledad
Castro Morera, Ana
author Sanz‑Gómez, Marta
author_facet Sanz‑Gómez, Marta
Aledavood, Elnaz
Beroiz‑Salaverri, Marina
Lagartera, Laura
Vega‑Martín, Elena
Gil‑Ortega, Marta
Cumella, Jose
Pérez, Concepción
Luque, F. Javier
Estarellas, Carolina
Fernández-Alfonso, María Soledad
Castro Morera, Ana
author_role author
author2 Aledavood, Elnaz
Beroiz‑Salaverri, Marina
Lagartera, Laura
Vega‑Martín, Elena
Gil‑Ortega, Marta
Cumella, Jose
Pérez, Concepción
Luque, F. Javier
Estarellas, Carolina
Fernández-Alfonso, María Soledad
Castro Morera, Ana
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Fundación Eugenio Rodríguez Pascual
Ministerio de Ciencia, Innovación y Universidades (España)
Ministerio de Economía y Competitividad (España)
Generalitat de Catalunya
Universidad Complutense de Madrid
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
description Endothelial adenosine monophosphate-activated protein kinase (AMPK) plays a critical role in the regulation of vascular tone through stimulating nitric oxide (NO) release in endothelial cells. Since obesity leads to endothelial dysfunction and AMPK dysregulation, AMPK activation might be an important strategy to restore vascular function in cardiometabolic alterations. Here, we report the identification of a novel AMPK modulator, the indolic derivative IND6, which shows affinity for AMPKα1β1γ1, the primary AMPK isoform in human EA.Hy926 endothelial cells. IND6 shows inhibitory action of the enzymatic activity in vitro, but increases the levels of p-Thr174AMPK, p-Ser1177eNOS and p-Ser79ACC in EA.Hy926. This paradoxical finding might be explained by the ability of IND6 to act as a mixed-type inhibitor, but also to promote the enzyme activation by adopting two distinct binding modes at the ADaM site. Moreover, functional assays reveal that IND6 increased the eNOS-dependent production of NO and elicited a concentration-dependent vasodilation of endothelium-intact rat aorta due to AMPK and eNOS activation, demonstrating a functional activation of the AMPK–eNOS–NO endothelial pathway. This kinase inhibition profile, combined with the paradoxical AMPK activation in cells and arteries, suggests that these new chemical entities may constitute a valuable starting point for the development of new AMPK modulators with therapeutic potential for the treatment of vascular complications associated with obesity.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/269579
url http://hdl.handle.net/10261/269579
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-095544-B-I00
https://doi.org/10.1038/s41598-022-07077-8
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
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