Resolvin E1 prevents doxorubicin-induced senescence in endothelial cells and cardiac fibroblasts
Aging is featured by the deterioration of body functions and has been related to an increased risk of developing cardiovascular diseases (CVD). One of the main characteristics of aging is cellular senescence (CS), defined as the irreversible cell cycle arrest and the acquisition of characteristic ph...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2022 |
| País: | Chile |
| OAI Identifier: | oai:repositorio.anid.cl:10533/42541 |
| Acceso en línea: | https://hdl.handle.net/10533/42541 |
| Access Level: | acceso abierto |
| Palabra clave: | Medicina y Ciencias de la Salud Medicina Básica Farmacología y Farmacia |
| Sumario: | Aging is featured by the deterioration of body functions and has been related to an increased risk of developing cardiovascular diseases (CVD). One of the main characteristics of aging is cellular senescence (CS), defined as the irreversible cell cycle arrest and the acquisition of characteristic phenotype in cells, including a secretome known as SASP through which a proinflammatory microenvironment is promoted and CS propagates. Doxorubicin (Doxo) is an antineoplastic with adverse cardiovascular effects that have limited its use. The mechanisms described that explain these effects are the increase in oxidative stress, inflammation, and the induction of CS. Interleukin (IL)-1β and the complex responsible for its production, the NLRP3 inflammasome, have been directly related both to the use of Doxo and to an increased risk of developing CVD. Endothelial cells (EC) and cardiac fibroblasts (CF) are the main non-muscle cell types of the cardiovascular system; the CS of these cells is related to a higher incidence of endothelial dysfunction and cardiac fibrosis, the main risk factors in the development of CVD. However, the mechanisms by which Doxo could be inducing CS of EC and CF are not fully understood and it is unknown whether IL-1β secretion through activation of the NLRP3 inflammasome could be involved. Various pharmacological strategies have been proposed to reduce the presence of senescent cells; however, resolvin E1 (RvE1), a lipid mediator with potent pro-resolution and anti-inflammatory effects, has not been studied in the prevention of Doxo-induced CS of EC and CF. The objective of this work was to study whether Doxo induces CS in EC and CF through IL-1β secretion and if RvE1 attenuates Doxo-induced CS by decreasing cytokine secretion. EC were isolated from human umbilical cord veins and CF from adult mice. Subsequently, the cells were stimulated with Doxo in the presence or absence of RvE1, MCC950 (inflammasome activation inhibitor NLRP3), and anakinra (IL-1 receptor antagonist) in EC or IR1A (endogenous IL-1 receptor antagonist) in CF. CS was evaluated by senescence-associated β-galactosidase activity (SA-β-gal), γH2A.X, p53, p21, and SASP. The most relevant results were: 1) Doxo induces CS of EC and CF by activating the NLRP3/IL-1 receptor inflammasome axis. 2) IL-1β in CF in turn induces CS and a strong increase in SASP in comparison with Doxo. 3) RvE1 attenuated Doxo-induced EC and CF senescence and IL-1β-induced CF senescence by decreasing IL-1β secretion. In conclusion, we can point out that RvE1 was able to counteract Doxo-induced senescence by decreasing IL-1β secretion. This raises RvE1 as a potential pharmacotherapeutic tool in cardiovascular protection against damage induced by Doxo, as well as in CVD with an important role of IL-1β. |
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