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...
| Autor: | |
|---|---|
| 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 |
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Resolvin E1 prevents doxorubicin-induced senescence in endothelial cells and cardiac fibroblasts Resolvina E1 previene la senescencia inducida por doxorrubicina en células endoteliales y fibroblastos cardiacos |
| title |
Resolvin E1 prevents doxorubicin-induced senescence in endothelial cells and cardiac fibroblasts |
| spellingShingle |
Resolvin E1 prevents doxorubicin-induced senescence in endothelial cells and cardiac fibroblasts Espitia-Corredor, Jenaro Antonio Medicina y Ciencias de la Salud Medicina Básica Farmacología y Farmacia |
| title_short |
Resolvin E1 prevents doxorubicin-induced senescence in endothelial cells and cardiac fibroblasts |
| title_full |
Resolvin E1 prevents doxorubicin-induced senescence in endothelial cells and cardiac fibroblasts |
| title_fullStr |
Resolvin E1 prevents doxorubicin-induced senescence in endothelial cells and cardiac fibroblasts |
| title_full_unstemmed |
Resolvin E1 prevents doxorubicin-induced senescence in endothelial cells and cardiac fibroblasts |
| title_sort |
Resolvin E1 prevents doxorubicin-induced senescence in endothelial cells and cardiac fibroblasts |
| dc.creator.en.fl_str_mv |
Espitia-Corredor, Jenaro Antonio |
| author |
Espitia-Corredor, Jenaro Antonio |
| author_facet |
Espitia-Corredor, Jenaro Antonio |
| author_role |
author |
| dc.contributor.advisor.en.fl_str_mv |
Díaz-Araya, Guillermo Peiró, Concepción |
| dc.contributor.institution.en.fl_str_mv |
UNIVERSIDAD DE CHILE |
| dc.subject.oecd1n.en.fl_str_mv |
Medicina y Ciencias de la Salud |
| topic |
Medicina y Ciencias de la Salud Medicina Básica Farmacología y Farmacia |
| dc.subject.oecd2n.en.fl_str_mv |
Medicina Básica |
| dc.subject.oecd3n.en.fl_str_mv |
Farmacología y Farmacia |
| description |
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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2022 |
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2022-09-05T14:29:52Z |
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2022-09-05T14:29:52Z |
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2022 |
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2023-05-30T12:23:41Z |
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2023-05-30T12:23:41Z |
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info:eu-repo/date/embargoEnd/2023-11-01 |
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info:eu-repo/semantics/doctoralThesis |
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Tesis |
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https://hdl.handle.net/10533/42541 |
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info:eu-repo/semantics/dataset/hdl.handle.net/10533/93488 |
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openAccess |
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UNIVERSIDAD DE CHILEEspitia-Corredor, Jenaro Antonio2022https://hdl.handle.net/10533/42541http://purl.org/coar/access_right/c_abf2Farmacología y FarmaciaMedicina BásicaMedicina y Ciencias de la SaludResolvin E1 prevents doxorubicin-induced senescence in endothelial cells and cardiac fibroblastsDíaz-Araya, GuillermoPeiró, ConcepciónUNIVERSIDAD DE CHILEChileEspitia-Corredor, Jenaro Antonio2022-09-05T14:29:52Z2023-05-30T12:23:41Z2022-09-05T14:29:52Z2023-05-30T12:23:41Zinfo:eu-repo/date/embargoEnd/2023-11-012022Aging 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.El envejecimiento se caracteriza por deterioro de las funciones del organismo y se ha relacionado con un mayor riesgo de desarrollar enfermedades cardiovasculares (ECV). Una de las características principales del envejecimiento es la senescencia celular (SC), definida como el arresto irreversible del ciclo celular y la adquisición de cambios fenotípicos característicos en las células, entre ellos un secretoma conocido como SASP mediante el cual se promueve un microambiente proinflamatorio y se propaga la SC. Doxorrubicina (Doxo) es un antineoplásico con efectos adversos a nivel cardiovascular que han limitado su uso; dentro de los mecanismos que explican estos efectos se describen el aumento de estrés oxidativo, inflamación y la inducción de SC. La interleuquina (IL)-1β y el complejo responsable de su producción, el inflamasoma NLRP3, han sido directamente relacionados tanto con el uso de Doxo como con un mayor riesgo de ECV. Células endoteliales (CE) y fibroblastos cardiacos (FC) son los principales tipos celulares no musculares del sistema cardiovascular; la SC de estas células está relacionada con una mayor incidencia de disfunción endotelial y fibrosis cardiaca, principales factores de riesgo en el desarrollo de ECV. Sin embargo, los mecanismos por los cuales Doxo podría estar induciendo la SC de CE y de FC no están completamente esclarecidos y se desconoce si la secreción de IL-1β mediante la activación del inflamasoma NLRP3 podría estar involucrada. Se han planteado diversas estrategias farmacológicas para disminuir la presencia de células senescentes; sin embargo, la resolvina E1 (RvE1), un mediador lipídico con potentes efectos pro-resolutivos y antiinflamatorios no ha sido estudiada en la prevención de la SC de CE y de FC inducida por Doxo. El objetivo de este trabajo fue estudiar si Doxo induce la SC en CE y FC a través de la secreción de IL-1β y, además, si la RvE1 atenúa la SC inducida por Doxo a través de la disminución dicha secreción. CE fueron aisladas de venas de cordón umbilical humano y FC de ratones adultos, posteriormente fueron estimuladas con Doxo en presencia o ausencia de la RvE1, del MCC950 (inhibidor de la activación del inflamasoma NLRP3) y de anakinra (antagonista del receptor de IL-1) en CE o de IR1A (antagonista endógeno del receptor de IL-1) en FC. Se evaluó SC mediante la actividad β-galactosidasa asociada a senescencia (SA-β-gal), γH2A.X, p53, p21 y el SASP. Los resultados más relevantes fueron: 1) Doxo induce senescencia de CE y FC mediante la activación del eje inflamasoma NLRP3/receptor IL-1. 2) IL-1β induce la senescencia en FC y a su vez un fuerte aumento del SASP en comparación con Doxo. 3) RvE1 atenuó la senescencia de CE y FC inducida por Doxo y de FC inducida por IL-1β disminuyendo la secreción de IL-1β. En conclusión, podemos señalar que RvE1 mostró ser capaz de contrarrestar la senescencia de CE y FC inducida por Doxo disminuyendo la secreción de IL-1β. Lo cual plantea a la RvE1 como una potencial herramienta farmacoterapéutica en la protección cardiovascular frente al daño inducido por Doxo, así como en ECV con un rol importante de la IL-1β.La Universidad de Chile liberará la publicación en la fecha mencionada de forma pública.21170233https://hdl.handle.net/10533/42541instname: Conicytreponame: Repositorio Digital RI2.0info:eu-repo/grantAgreement//21170233info:eu-repo/semantics/dataset/hdl.handle.net/10533/93488Attribution-NonCommercial-NoDerivs 3.0 Chileinfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by-nc-nd/3.0/cl/Medicina y Ciencias de la SaludMedicina BásicaFarmacología y FarmaciaResolvin E1 prevents doxorubicin-induced senescence in endothelial cells and cardiac fibroblastsResolvina E1 previene la senescencia inducida por doxorrubicina en células endoteliales y fibroblastos cardiacosinfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionTesisTesishttps://hdl.handle.net/10533/42541567f3d73-1a80-4f7d-9ea5-bf8b10371835virtual::79774-1567f3d73-1a80-4f7d-9ea5-bf8b10371835virtual::79774-1ORIGINALTesis Doctorado - Jenaro Antonio ...application/octet-stream31361https://repositorio.anid.cl/bitstreams/ec10764d-37a8-4c55-8186-029a1d406276/download89dd671e1830f3dce5d1381047a58b91MD5110533/42541oai:repositorio.anid.cl:10533/425412024-01-17 16:11:15.806http://creativecommons.org/licenses/by-nc-nd/3.0/cl/info:eu-repo/semantics/embargoedAccesshttps://repositorio.anid.clRepositorio ANIDaletelier@anid.cl |
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15,81155 |