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https://doi.org/10.21203/rs.3.rs-4358850/v1


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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