Key result
Resolvin E1 prevents doxorubicin-induced cardiac fibroblast senescence by reducing IL-1β secretion.
Why the study?
Doxorubicin induces cardiac fibroblast senescence via mechanisms that are not fully understood, and whether Resolvin E1 can prevent this senescence had not been previously investigated.
Does Resolvin E1 prevent doxorubicin-induced senescence in murine cardiac fibroblasts?
Does Resolvin E1 prevent doxorubicin-induced senescence in murine cardiac fibroblasts?
Resolvin E1 prevents doxorubicin-induced senescence in murine cardiac fibroblasts, suggesting a potential therapeutic strategy to mitigate doxorubicin cardiotoxicity.
Hypothesis-generating for Resolvin E1 against doxorubicin cardiotoxicity; leaves open translation to human therapy.
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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Espitia-Corredor et al. (2022) studied Doxorubicin-induced cardiac fibroblast senescence. Resolvin E1 (RvE1) vs. Doxorubicin alone was evaluated on Senescence markers (SA-β-gal, γ-H2A.X, p53, p21, and SASP). Resolvin E1 prevented doxorubicin-induced cardiac fibroblast senescence, an effect likely mediated by reducing IL-1β secretion.
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