Resolvin E1 attenuates doxorubicin-induced cardiac fibroblast senescence: A key role for IL-1β
10.1016/j.bbadis.2022.166525BBA - Molecular Basis of Disease 1868.11 (2022): 166525
Funded byThis study was supported by PID2020-115590RB-100/AEI/ 10.13039/501100011033 and FONDECYT 1210627 to C.P., C.F.S.F., and G.D.A., respectively. L.S. and J.A.E.C. are the recipients of FPI Universidad Autonoma ´ de Madrid (SFPI/2020-00053) and Beca Doctorado Nacional Ano ˜ 2017 ANID (21170233) fellowships, respectively
SubjectsCardiac fibroblasts; Doxorubicin; Interleukin-1β; Resolvin E1; Senescence; Farmacia
Rights© 2022 The Author(s)
Esta obra está bajo una Licencia Creative Commons Atribución 4.0 Internacional.
Cardiac fibroblasts (CFs) undergo senescence in reaction to different stressors, leading to a poor prognosis of cardiac disease. Doxorubicin (Doxo) is an antineoplastic drug with strong cardiotoxic effects, which induces IL-1β secretion and thus, triggers a potent pro-inflammatory response. Doxo induces CFs senescence; however, the mechanisms are not fully understood. Different pharmacological strategies have been used to eliminate senescent cells by inducing their apoptosis or modifying their secretome. However, Resolvin E1 (RvE1), a lipid derivative resolutive mediator with potent anti-inflammatory effects has not been used before to prevent CFs senescence. CFs were isolated from adult male C57BL/6J mice and subsequently stimulated with Doxo, in the presence or absence of RvE1. Senescence-associated β-galactosidase activity (SA-β-gal), γ-H2A.X, p53, p21, and senescence-associated secretory phenotype (SASP) were evaluated. The involvement of the NLRP3 inflammasome/interleukin-1 receptor (IL-1R) signaling pathway on CFs senescence was studied using an NLRP3 inhibitor (MCC950) and an endogenous IL-1R antagonist (IR1A). Doxo is able to trigger CFs senescence, as evidenced by an increase of γ-H2A.X, p53, p21, and SA-β-gal, and changes in the SASP profile. These Doxo effects were prevented by RvE1. Doxo triggers IL-1β secretion, which was dependent on NLRP3 activation. Doxo-induced CFs senescence was partially blocked by MCC950 and IR1A. In addition, IL-1β also triggered CFs senescence, as evidenced by the increase of γ-H2A.X, p53, p21, SA-β-gal activity, and SASP. All these effects were also prevented by RvE1 treatment. Conclusion: These data show the anti-senescent role of RvE1 in Doxo-induced CFs senescence, which could be mediated by reducing IL-1β secretion.
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Google Scholar:Espitia Corredor, Jenaro A. - Shamoon, Licia - Olivares Silva, Francisco - Rimassa Taré, Constanza - Muñoz Rodríguez, Claudia - Espinoza Pérez, Claudio - Sánchez Ferrer, Carlos F. - Peiró Vallejo, M. Concepción - Díaz Araya, Guillermo
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