1. Activation of p62-NRF2 Axis Protects against Doxorubicin-Induced Ferroptosis in Cardiomyocytes: A Novel Role and Molecular Mechanism of Resveratrol.
- Author
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Yu, Wei, Chen, Chunjuan, Xu, Chenxi, Xie, De, Wang, Qiang, Liu, Weidong, Zhao, Hairong, He, Furong, Chen, Bingyang, Xi, Yuemei, Yan, Yunbo, Yu, Linqian, and Cheng, Jidong
- Subjects
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HEART metabolism , *CARDIOTOXICITY , *IN vitro studies , *GLUTATHIONE , *HEART cells , *IN vivo studies , *CELL culture , *DOXORUBICIN , *NUCLEAR factor E2 related factor , *ANIMAL experimentation , *WESTERN immunoblotting , *ONE-way analysis of variance , *SMALL interfering RNA , *RESVERATROL , *OXIDATIVE stress , *CELL survival , *ELECTRON microscopy , *MALONDIALDEHYDE , *COMPARATIVE studies , *T-test (Statistics) , *ELECTROCARDIOGRAPHY , *DESCRIPTIVE statistics , *DATA analysis software , *CELL death , *MICE , *LIPID peroxidation (Biology) - Abstract
Doxorubicin (DOX) is a most common anthracycline chemotherapeutic agent; however, its clinical efficacy is limited due to its severe and irreversible cardiotoxicity. Ferroptosis, characterized by iron overload and lipid peroxidation, plays a pivotal role in DOX-induced cardiotoxicity. Resveratrol (RSV) displays cardioprotective and anticancer effects, owing to its antioxidative and anti-inflammatory properties. However, the role and mechanism of RSV in DOX-mediated ferroptosis in cardiomyocytes is unclear. This study showed that DOX decreased cell viability, increased iron accumulation and lipid peroxidation in H9c2 cells; however, these effects were reversed by RSV and ferroptosis inhibitor ferrostatin-1 (Fer-1) pre-treatment. Additionally, RSV significantly increased the cell viability of H9c2 cells treated with ferroptosis inducers Erastin (Era) and RSL3. Mechanistically, RSV inhibited mitochondrial reactive oxygen species (mtROS) overproduction and upregulated the p62-NRF2/HO-1 pathway. RSV-induced NRF2 activation was partially dependent on p62, and the selective inhibition of p62 (using p62-siRNA interference) or NRF2 (using NRF2 specific inhibitor, ML385) significantly abolished the anti-ferroptosis function of RSV. Furthermore, RSV treatment protected mice against DOX-induced cardiotoxicity, including significantly improving left ventricular function, ameliorating myocardial fibrosis and suppressing ferroptosis. Consistent with in vitro results, RSV also upregulated the p62-NRF2/HO-1 expression, which was inhibited by DOX, in the myocardium. Notably, the protective effect of RSV in DOX-mediated ferroptosis was similar to that of Fer-1 in vitro and in vivo. Thus, the p62-NRF2 axis plays a critical role in regulating DOX-induced ferroptosis in cardiomyocytes. RSV as a potent p62 activator has potential as a therapeutic target in preventing DOX-induced cardiotoxicity via ferroptosis modulation. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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