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Título: AEOL-Induced NRF2 Activation and DWORF Overexpression Mitigate Myocardial I/R Injury
Fecha de publicación: 15-may-2024
Cita bibliográfica: Research Square, 2024
ISSN: Electronic: 2693-5015
Palabras clave: Acute myocardial infarction
Reperfusion injury
NFR2
SERCA2a
PLN
Resumen: The causal relationship between the activation of NRF2 and the preservation of SERCA2a function in mitigating myocardial ischemia-reperfusion (mI/R) injury, along with the associated regulatory mechanisms, remains incompletely understood. The aim of this study was to characterize this relationship by testing the pharmacological repositioning of AEOL-10150 (AEOL) as a novel NRF2 activator. C57BL6/J, Nrf2 knockout (Nrf2−/−), and wild-type (Nrf2+/+) mice, as well as human induced pluripotent stem cell-derived cardiomyocytes (hiPSCMs) were subjected to I/R injury. Gain/loss of function techniques, RT-qPCR, western blotting, LC/MS/MS, and fluorescence spectroscopy were utilized. Cardiac dimensions and function were assessed by echocardiography. In the early stages of mI/R injury, AEOL administration reduced mitochondrial ROS production, decreased myocardial infarct size, and improved cardiac function. These effects were due to NRF2 activation, leading to the overexpression of the micro-peptide DWORF, consequently enhancing SERCA2a activity. The cardioprotective effect induced by AEOL was diminished in Nrf2−/− mice and in Nrf2/Dworf knockdown models in hiPSCMs subjected to simulated I/R injury. Our data show that AEOL-induced NRF2-mediated upregulation of DWORF disrupts the phospholamban-SERCA2a interaction, leading to enhanced SERCA2a activation and improved cardiac function. Taken together, our study reveals that AEOL-induced NRF2-mediated overexpression of DWORF enhances myocardial function through the activation of the SERCA2a offering promising therapeutic avenues for mI/R injury.
Autor/es principal/es: Lax Pérez, Antonio Manuel
Asensio López, María del Carmen
Ruiz Ballester, Miriam
Pascual Oliver, Silvia
Fernández del Palacio, María Josefa
Sassi, Yassine
Fuster, Jose Javier
Pascual Figal, Domingo
Soler, Fernando
Versión del editor: https://www.researchsquare.com/article/rs-4358850/v1
URI: http://hdl.handle.net/10201/143111
DOI: https://doi.org/10.21203/rs.3.rs-4358850/v1
Tipo de documento: info:eu-repo/semantics/article
Derechos: info:eu-repo/semantics/openAccess
Atribución 4.0 Internacional
Descripción: © Research Square 2024. This manuscript version is made available under the CC-BY 4.0 license http://creativecommons.org/licenses/by/4.0/ This document is the Submitted version of a no Published Work.
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