RT Journal Article
T1 Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK-eNOS-NO pathway
A1 Sanz Gómez, Marta
A1 Aledavood, Elnaz
A1 Beroiz Salaverri, Marina
A1 Lagartera, Laura
A1 Vega Martín, Elena
A1 Gil Ortega, Marta
A1 Cumella, José
A1 Pérez, Concepción
A1 Luque, Francisco Javier
A1 Estarellas, Carolina
A1 Castro, Ana
A1 Fernández Alfonso, María Soledad
AB 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 identifcation of a novel AMPK modulator, the indolic derivative IND6, which shows afnity 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 fnding 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 aortadue to AMPK and eNOS activation, demonstrating a functional activation of the AMPK–eNOS–NO endothelial pathway. This kinase inhibition profle, 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.
YR 2022
FD 2022
LK https://hdl.handle.net/20.500.14352/93790
UL https://hdl.handle.net/20.500.14352/93790
LA eng
NO Sanz-Gómez M, Aledavood E, Beroiz-Salaverri M, Lagartera L, Vega-Martín E, Gil-Ortega M, et al. Novel indolic AMPK modulators induce vasodilatation through activation of the AMPK–eNOS–NO pathway. Sci Rep 2022;12:4225. https://doi.org/10.1038/s41598-022-07077-8.
NO Fundación Eugenio Rodríguez Pascual
NO Ministerio de Economía y Competitividad (España)
NO Ministerio de Ciencia Innovación y Universidades (España)
NO Generalitat de Catalunya
NO Barcelona Supercomputing Center
NO Consorci de Serveis Universitaris de Catalunya
NO Agencia de Gestión de Ayudas Universitarias y de Investigación
DS Docta Complutense
RD 9 abr 2025