Artículos de revistas
Pharmacological blockade of NLRP3 inflammasome/IL1β-positive loop mitigates endothelial cell senescence and dysfunction
Fecha
2022Registro en:
Aging and Disease (2022) 13:284-297
10.14336/AD.2021.0617
Autor
Romero, Alejandra
Dongil, Pilar
Valencia, Inés
Vallejo, Susana
San Hipólito Luengo, Álvaro
Díaz Araya, Guillermo
Bartha, José L.
González Arlanzón, María M.
Rivilla, Fernando
Cuesta, Fernando de la
Sánchez Ferrer, Carlos
Peiró, Concepción
Institución
Resumen
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.