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Updated: Jul 16, 2025
A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Oridonin ameliorates doxorubicin induced-cardiotoxicity via the E2F1/Sirt6/PGC1α pathway in mice
Dongsheng Yu1, Jiye Li2, Yu Wang1
1Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, China.
Abstract:
Doxorubicin induced cardiotoxicity (DIC) arises from mitochondrial dysfunction and oxidative stress. Oridonin (Ori), a natural tetracycline diterpenoid, has shown cardiac protective effect; however, its role in DIC remains unclear. This study investigates the protective effect of Ori against DIC and elucidates its underlying molecular mechanisms. The results demonstrate that Ori significantly alleviated DIC by improving myocardial structure, reducing the proportion of apoptotic cells, and alleviating the myocardial oxidative damage and mitochondrial dysfunction both in vivo and in vitro. Doxorubicin significantly decreased Sirt6 and PGC1α levels in cardiac tissues, which was reversed by Ori. Furthermore, Sirt6 overexpression significantly improved myocardial structure and reduced the proportion of apoptotic cells by reducing oxidative stress and improving mitochondrial function. The protective effect of Ori is neutralized by the Sirt6 inhibitor OSS_128167, evidenced by downregulated mRNA and protein expression of PGC1α. The transcription factor E2F1 was upregulated by doxorubicin, leading to decreased Sirt6 expression-an effect mitigated by Ori. Molecular docking simulations indicate direct binding between Ori and specific amino acid residues on E2F1 through hydroxyl bonds. These findings uncover a novel mechanism whereby Ori attenuates DIC by modulating the E2F1/Sirt6/PGC1α pathway.
Insights
Oridonin protects the heart from doxorubicin-induced cardiotoxicity by improving mitochondrial function and reducing oxidative stress. This natural compound modulates the E2F1/Sirt6/PGC1α pathway to achieve its protective effects.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Doxorubicin-induced cardiotoxicity (DIC) is a significant clinical challenge.
- Mitochondrial dysfunction and oxidative stress are key mechanisms underlying DIC.
- Oridonin (Ori) is a natural compound with potential cardioprotective properties, but its role in DIC is not well understood.
Purpose of the Study:
- To investigate the protective effects of Oridonin against doxorubicin-induced cardiotoxicity.
- To elucidate the molecular mechanisms underlying Oridonin's cardioprotective action in DIC.
Main Methods:
- In vivo and in vitro studies using Doxorubicin and Oridonin.
- Assessment of myocardial structure, apoptosis, oxidative damage, and mitochondrial function.
- Analysis of Sirt6, PGC1α, and E2F1 expression levels.
- Inhibition of Sirt6 activity and molecular docking simulations.
Main Results:
- Oridonin significantly alleviated DIC, improving myocardial structure and reducing apoptosis, oxidative stress, and mitochondrial dysfunction.
- Oridonin reversed Doxorubicin-induced decreases in Sirt6 and PGC1α levels.
- Sirt6 overexpression mimicked Oridonin's protective effects, while Sirt6 inhibition abolished them.
- Oridonin mitigated Doxorubicin-induced E2F1 upregulation, with molecular docking suggesting direct binding between Oridonin and E2F1.
Conclusions:
- Oridonin exerts significant cardioprotective effects against Doxorubicin-induced cardiotoxicity.
- The protective mechanism involves the modulation of the E2F1/Sirt6/PGC1α pathway.
- Oridonin represents a potential therapeutic agent for preventing or treating Doxorubicin-induced cardiotoxicity.
