2026-06-14T06:44:28Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/268432025-12-18T13:01:55Zcom_20.500.12105_19586com_20.500.12105_2202col_20.500.12105_19587
Repisalud
author
Asensio-Lopez, Maria Del Carmen
author
Ruiz-Ballester, Miriam
author
Pascual-Oliver, Silvia
author
Bastida-Nicolas, Francisco Jose
author
Sassi, Yassine
author
Fuster, Jose Javier
author
Pascual-Figal, Domingo
author
Soler, Fernando
author
Lax, Antonio
funder
Fundación Mutua Madrileña
funder
Instituto de Salud Carlos III
funder
Unión Europea. Fondo Social Europeo (ESF/FSE)
funder
Ministerio de Ciencia, Innovación y Universidades (España)
funder
Fundación ProCNIC
funder
Ministerio de Ciencia e Innovación. Centro de Excelencia Severo Ochoa (España)
2025-07-23T12:46:33Z
2025-07-23T12:46:33Z
2025-05-15
Mol Med. 2025 May 15;31(1):189.
Molecular Medicine
40375185
https://hdl.handle.net/20.500.12105/26843
The causal relationship between the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and the preservation of SERCA2a function in mitigating myocardial ischemia-reperfusion (mI/R) injury, along with the associated regulatory mechanisms, remains incompletely understood. This study aims to unravel how NRF2 directly or indirectly influences SERCA2a function and its regulators, phospholamban (PLN) and Dwarf Open Reading Frame (DWORF), by testing the pharmacological repositioning of AEOL-10150 (AEOL) in the context of mI/R injury. 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.
eng
AEOL-10150
Acute myocardial infarction
Cardiac protection
DWORF
NRF2
Reperfusion injury
AEOL-induced NRF2 activation and DWORF overexpression mitigate myocardial I/R injury.
research article
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URL
https://repisalud.isciii.es/bitstreams/6555d0f3-8c69-44d1-b437-d82f5881bbd4/download
File
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68c8730a9175280a38d94953876f652f
4916493
application/pdf
AEOL-induced NRF2_Mol Med_2025.pdf