Evaluación del efecto directo de la Doxorrubicina en cardiomiocitos ventriculares aislados de cobayo (Cavia porcellus) sobre la expresión del canal de potasio sensible a ATP (KATP) y de miRNAs que se asocien con su regulación

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dc.contributor.advisorGomez Grosso, Luis Albertospa
dc.contributor.authorDomínguez Romero , Leidy Yohanaspa
dc.contributor.researchgroupGrupo de Fisiología Molecularspa
dc.date.accessioned2025-09-09T19:03:46Z
dc.date.available2025-09-09T19:03:46Z
dc.date.issued2025-09-01
dc.descriptionilustraciones, diagramasspa
dc.description.abstractLa doxorrubicina (DOX) es un quimioterapéutico ampliamente utilizado cuyo principal efecto adverso es la cardiotoxicidad, lo que limita su aplicación clínica. Sin embargo, los mecanismos moleculares subyacentes a este efecto, especialmente en relación con la regulación mediada por microRNAs (miRNAs) y los sistemas endógenos de cardioprotección, no han sido completamente dilucidados. El objetivo de este estudio fue evaluar la expresión del canal de potasio sensible al ATP (KATP) y ciertos miRNAs específicos relacionados con su regulación en cardiomiocitos ventriculares de cobayos expuestos a DOX. Los cardiomiocitos fueron aislados mediante perfusión retrógrada y expuestos a 10 μM de DOX, observándose una disminución significativa del acortamiento celular y del ATP intracelular, junto con un aumento de especies reactivas de oxígeno (ROS), calcio citosólico (Ca²⁺) y despolarización mitocondrial. El perfil de expresión de miRNAs se determinó mediante Secuenciación de Nueva Generación (NGS), y se validó la expresión diferencial de miR-27a-5p, miR-99b-5p, miR-133a, miR-181a-5p y miR-34a-5p por stem loop RT-qPCR. Asimismo, se detectaron alteraciones en la expresión de las subunidades del canal KATP (ABCC9, KCNJ8, KCNJ11) y de genes asociados a cardioprotección como FoxO1, SIRT1 y GSK3β, tanto a nivel de RNA como de proteína mediante RT-qPCR y Western Blot respectivamente. Los análisis de correlación y redes reguladoras sugieren que algunos miRNAs se asocian positiva o negativamente con la expresión de KATP y proteínas cardioprotectoras como FOXO1, SIRT1 y GSK3β, evidenciando que la DOX altera mecanismos endógenos de protección cardíaca. Estos hallazgos contribuyen a una mejor comprensión de la fisiopatología de la Cardiotoxicidad Inducida por Doxorrubicina (CID) y abren nuevas perspectivas para el desarrollo de estrategias terapéuticas y la evaluación de estos miRNAs como candidatos a biomarcadores de detección temprana que permitan prevenir o mitigar el daño cardíaco asociado a este fármaco. (Texto tomado de la fuente).spa
dc.description.abstractDoxorubicin (DOX) is a widely used chemotherapeutic agent whose main adverse effect is cardiotoxicity, limiting its clinical application. However, the underlying molecular mechanisms of this effect, particularly those related to microRNA (miRNA)-mediated regulation and endogenous cardioprotective systems, have not been fully elucidated. The aim of this study was to evaluate the expression of the ATP-sensitive potassium channel (KATP) and specific miRNAs related to its regulation in ventricular cardiomyocytes from guinea pigs exposed to DOX. Cardiomyocytes were isolated by retrograde perfusion and exposed to 10 µM DOX, resulting in a significant decrease in cell shortening and intracellular ATP, along with increased Reactive Oxygen Species (ROS), cytosolic calcium, and mitochondrial depolarization. The miRNA expression profile was determined by NextGeneration Sequencing (NGS), and the differential expression of miR-27a-5p, miR-99b-5p, miR-133a, miR-181a-5p, and miR-34a-5p was validated by stem-loop RT-qPCR. In addition, alterations were detected in the expression of KATP channel subunits (ABCC9, KCNJ8, KCNJ11) and cardioprotective genes such as FoxO1, SIRT1, and GSK3β, both at the RNA and protein levels, using RT-qPCR and Western blot, respectively. Correlation and regulatory network analyses suggest that some miRNAs are positively or negatively associated with the expression of KATP and cardioprotective proteins such as FoxO1, SIRT1, and GSK3β, indicating that DOX disrupts endogenous cardiac protection mechanisms. These findings contribute to a better understanding of the pathophysiology of doxorubicin-induced cardiotoxicity and open new perspectives for the development of therapeutic strategies and the evaluation of these miRNAs as potential early detection biomarkers to prevent or mitigate the cardiac damage associated with this drug.eng
dc.description.degreelevelDoctoradospa
dc.description.degreenameDoctor en Biotecnologíaspa
dc.description.methodsEsta es una investigación biomédica experimental in vitro basada en el uso de cardiomiocitos ventriculares aislados de corazones de cobayos Hartley, Cavia porcellus . Este modelo es muy útil en la investigación de la fisiología celular y molecular cardiaca permitiendo evaluar el efecto de diferentes agentes cardiotóxicos o cardioprotectores de manera directaspa
dc.description.researchareaMecanismos celulares y moleculares de cardioprotecciónspa
dc.format.extent158 páginasspa
dc.format.mimetypeapplication/pdf
dc.identifier.instnameUniversidad Nacional de Colombiaspa
dc.identifier.reponameRepositorio Institucional Universidad Nacional de Colombiaspa
dc.identifier.repourlhttps://repositorio.unal.edu.cospa
dc.identifier.urihttps://repositorio.unal.edu.co/handle/unal/88675
dc.language.isospa
dc.publisherUniversidad Nacional de Colombiaspa
dc.publisher.branchUniversidad Nacional de Colombia - Sede Bogotáspa
dc.publisher.facultyFacultad de Cienciasspa
dc.publisher.placeBogotá, Colombiaspa
dc.publisher.programBogotá - Ciencias - Doctorado en Biotecnologíaspa
dc.relation.indexedBiremespa
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dc.rights.accessrightsinfo:eu-repo/semantics/openAccess
dc.rights.licenseAtribución-NoComercial-SinDerivadas 4.0 Internacional
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.ddc570 - Biología::572 - Bioquímicaspa
dc.subject.ddc610 - Medicina y salud::616 - Enfermedadesspa
dc.subject.decsCanales KATPspa
dc.subject.decsKATP Channelseng
dc.subject.decsCardiotoxicidadspa
dc.subject.decsCardiotoxicityeng
dc.subject.decsMicroARNsspa
dc.subject.decsMicroRNAseng
dc.subject.decsMiocitos Cardíacosspa
dc.subject.decsMyocytes, Cardiaceng
dc.subject.proposalCardiomiocitosspa
dc.subject.proposalMicroRNAsspa
dc.subject.proposalKATPspa
dc.subject.proposalCardiomiocitosspa
dc.subject.proposalCardioprotecciónspa
dc.subject.proposalCardiotoxicidadspa
dc.subject.proposalDoxorubicineng
dc.subject.proposalMicroRNAseng
dc.subject.proposalKATPeng
dc.subject.proposalCardiomyocyteseng
dc.subject.proposalCardioprotectioneng
dc.titleEvaluación del efecto directo de la Doxorrubicina en cardiomiocitos ventriculares aislados de cobayo (Cavia porcellus) sobre la expresión del canal de potasio sensible a ATP (KATP) y de miRNAs que se asocien con su regulaciónspa
dc.title.translatedEvaluation of the direct effect of doxorubicin on isolated ventricular cardiomyocytes from Guinea Pig (Cavia porcellus) on the expression of the ATP-sensitive potassium channel (KATP) and miRNAs ociated with Its Regulationeng
dc.typeTrabajo de grado - Doctoradospa
dc.type.coarhttp://purl.org/coar/resource_type/c_db06
dc.type.coarversionhttp://purl.org/coar/version/c_ab4af688f83e57aa
dc.type.contentText
dc.type.driverinfo:eu-repo/semantics/doctoralThesis
dc.type.redcolhttp://purl.org/redcol/resource_type/TD
dc.type.versioninfo:eu-repo/semantics/acceptedVersion
dcterms.audience.professionaldevelopmentInvestigadoresspa
dcterms.audience.professionaldevelopmentEstudiantesspa
dcterms.audience.professionaldevelopmentMaestrosspa
oaire.accessrightshttp://purl.org/coar/access_right/c_abf2
oaire.fundernameInstituto Nacional de Saludspa
oaire.fundernameMinicienciasspa

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