Resolvin E1 attenuates endothelial senescence induced by doxorubicin through the modulation of NLRP3 inflammasome activation.
Authors:   Department of Pharmacology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain., Shamoon Licia ,   PhD Programme in Pharmacology and Physiology, Doctoral School, Universidad Autónoma de Madrid, Madrid, Spain.,   Instituto de Investigaciones Sanitarias (IdiPAZ), Madrid, Spain., Espitia-Corredor Jenaro A ,   Department of Pharmacology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.,   PhD Programme in Pharmacology and Physiology, Doctoral School, Universidad Autónoma de Madrid, Madrid, Spain.,   Laboratorio de Farmacología Molecular (FARMOLAB), Department of Pharmaceutical and Toxicological Chemistry, Faculty of Chemical Sciences and Pharmacy, Universidad de Chile, Santiago, Chile., Dongil Pilar ,   Department of Pharmacology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.,   Instituto de Investigaciones Sanitarias (IdiPAZ), Madrid, Spain., Menéndez-Ribes Marta ,   Department of Pharmacology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.,   Instituto de Investigaciones Sanitarias (IdiPAZ), Madrid, Spain., Romero Alejandra ,   Department of Pharmacology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.,   Instituto de Investigaciones Sanitarias (IdiPAZ), Madrid, Spain., Valencia Inés ,   Department of Pharmacology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.,   Instituto de Investigaciones Sanitarias (IdiPAZ), Madrid, Spain., Díaz- Araya Guillermo ,   Laboratorio de Farmacología Molecular (FARMOLAB), Department of Pharmaceutical and Toxicological Chemistry, Faculty of Chemical Sciences and Pharmacy, Universidad de Chile, Santiago, Chile.,   Advanced Center for Chronic diseases ACCDiS, Universidad de Chile, Santiago, Chile., Sánchez-Ferrer Carlos F ,   Department of Pharmacology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.,   Instituto de Investigaciones Sanitarias (IdiPAZ), Madrid, Spain., Peiró Concepción ,   Department of Pharmacology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain.,   Instituto de Investigaciones Sanitarias (IdiPAZ), Madrid, Spain.
Published: June 2022

Introduction: Vascular aging is associated with endothelial cell senescence, favoring low-grade inflammation, endothelial dysfunction, and cardiovascular diseases. Cell senescence arises from a wide variety of endogenous and exogenous stressors including some anticancer agents such as doxorubicin. Recently, doxorubicin was linked to the innate immunity component NLRP3 inflammasome which is implicated in many vascular inflammatory disorders. There is a need for therapeutic tools to help cancer patients who have been exposed to cardiovascular toxic chemotherapy averting premature vascular complications. We investigated whether resolvin E1 (RvE1), an endogenous lipid mediator of the inflammation resolution phase, could prevent doxorubicin-induced senescence in cultured human umbilical veins endothelial cells (HUVEC) with focus on a potential involvement of the NLRP3 inflammasome. Materials and Methods: Cell senescence was quantified by senescence-associated-β-galactosidase (SA-β-gal) staining. The expression of senescence markers (γH2AX, p21, p53) and inflammatory markers (pP65, NLRP3) was determined via Western blot. NLRP3 inflammasome activation was determined by visualizing the formation of ASC specks by indirect immunofluorescence. Results: Doxorubicin (25 nmol/L) augmented the number of SA-β-gal positive HUVEC and the levels of γH2AX, p21 and p53 which were all reduced by RvE1 (10 nmol/L). In doxorubicin-treated cells, RvE1 further reduced the expression of pP65 and NLRP3 proteins and the formation of ASC specks as did the inflammasome assembly inhibitor MCC950 (1µmol/L). Additionally, both MCC950 and interleukin-1 receptor inhibitor anakinra diminished SA-β-gal positive staining induced by doxorubicin. Conclusion: RvE1 offers a novel therapeutic approach against doxorubicin-induced cardiovascular toxicity and subsequent age-related vascular disorders by counteracting endothelial senescence through the modulation of NLRP3- inflammasome activation.