Pharmacological blockade of NLRP3 inflammasome/IL1β-positive loop mitigates endothelial cell senescence and dysfunction
Author
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Romero, Alejandra
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Dongil, Pilar
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Valencia, Inés
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Vallejo, Susana
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San Hipólito Luengo, Álvaro
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Díaz Araya, Guillermo
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Bartha, José L.
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González Arlanzón, María M.
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Rivilla, Fernando
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Cuesta, Fernando de la
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Sánchez Ferrer, Carlos
Author
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Peiró, Concepción
Admission date
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2022-07-15T14:11:07Z
Available date
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2022-07-15T14:11:07Z
Publication date
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2022
Cita de ítem
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Aging and Disease (2022) 13:284-297
es_ES
Identifier
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10.14336/AD.2021.0617
Identifier
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https://repositorio.uchile.cl/handle/2250/186749
Abstract
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The clinical relevance of IL-1 beta in chronic inflammation underlying atherosclerosis has been reinforced by recent evidence associating pharmacological inhibition of the cytokine with lower cardiovascular risk. Previously, we have demonstrated a direct involvement of IL-1 beta in endothelial senescence. Therefore, this can be a key mechanism contributing to the sterile inflammatory milieu associated with aging, termed inflammaging. In the present study, we have evaluated whether a positive feedback of IL-1 beta in the NLRP3 inflammasome via NF-kappa B could promote human endothelial senescence in vitro and murine endothelial dysfunction in vivo. Our results indicate that the NLRP3 inflammasome is pivotal in mediating the detrimental effects of IL-1 beta, showing that auto-activation is a crucial feature boosting endothelial cell senescence in vitro, which is paralleled by vascular dysfunction in vivo. Hence, the inhibitor of NLRP3 inflammasome assembly, MCC 950, was able to disrupt the aforementioned positive loop, thus alleviating inflammation, cell senescence and vascular dysfunction. Besides, we explored alternative NLRP3 inflammasome inhibitory agents such as the RAS heptapeptide Ang-(1-7) and the anti-aging protein klotho, both of which demonstrated protective effects in vitro and in vivo. Altogether, our results highlight a fundamental role for the hereby described NLRP3 inflammasome/IL-1 beta positive feedback loop in stress-induced inflammaging and the associated vascular dysfunction, additionally providing evidence of a potential therapeutic use of MCC 950, Ang-(1-7) and recombinant klotho to block this loop and its deleterious effects.
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Patrocinador
dc.description.sponsorship
Comunidad de Madrid 2019-T1/IND-13794
PEJ-2018-AI/SAL-9955
Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)
CONICYT FONDECYT 1130300
European Social Fund (ESF)
FPU-MECD fellowship FPU16/02612
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Lenguage
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en
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Publisher
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International Society on Aging and Disease
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Type of license
dc.rights
Attribution-NonCommercial-NoDerivs 3.0 United States