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Metformin Attenuates Myocardial Ischemia/Reperfusion-Induced Ferroptosis by Facilitating Nur77-Mediated IDH1 Upregulation

Harvard Dataverse (Africa Rice Center, Bioversity International, CCAFS, CIAT, IFPRI, IRRI and WorldFish)

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Title Metformin Attenuates Myocardial Ischemia/Reperfusion-Induced Ferroptosis by Facilitating Nur77-Mediated IDH1 Upregulation
 
Identifier https://doi.org/10.7910/DVN/GJYCE7
 
Creator Wu, Zhenhua
 
Publisher Harvard Dataverse
 
Description Abstract
This study aims to delve deeper into Metformin (Met)'s cardioprotective mechanisms, particularly its influence on the Nur77-IDH1 axis, expanding upon its established AMPKα-mediated benefits. We employed myocardial ischemia/reperfusion animal models and oxygen-glucose deprivation/reoxygenation in H9C2 cells, utilizing staining techniques, echocardiography, and molecular assays to assess ferroptosis indicators, mitochondrial function, and key proteins like Nur77 and IDH1, elucidating Metformin's cardioprotective pathways. Metformin significantly mitigated myocardial I/R injury in rats, reducing PTGS2 expression, iron and ROS accumulation, and enhancing ATP production and mitochondrial function. It alleviated myocardial tissue damage and fibrosis, and increased survival rates. In OGD/R-induced H9C2 cells, Metformin suppressed ferroptosis, an effect reversed by Nur77 silencing. It increased Nur77 and IDH1 expression and promoted Nur77's nuclear transfer, binding to the IDH1 promoter. Metformin also deactivated the JNK/P38 pathway. However, the IDH1 inhibitor compound 2 negated Metformin's anti-ferroptotic effects, underscoring IDH1's role in this process. Complementary to our previous study, here we suggest that Metformin combats myocardial ischemia/reperfusion injury by inhibiting ferroptosis. The proposed mechanism involves Metformin facilitating Nur77's nuclear transfer, enhancing IDH1 expression, and subsequently inactivating the JNK/P38 pathway. This insight not only underscores Met's potential in myocardial I/R treatment but also highlights the therapeutic value of targeting ferroptosis in heart protection strategies.
 
Subject Medicine, Health and Life Sciences
Metformin
Ferroptosis
 
Date 2024-02-06
 
Contributor Wu, Zhenhua