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Ginkgetin Alleviates Doxorubicin-Induced Heart Failure by Regulating Mitochondrial Dysfunction Through the
Yanfu Wang1, Chong Wang2, Wei Li1
1Department of Cardiovascular Medicine, Aviation General Hospital, Beijing, China.
Insights
Ginkgetin (GK) protects the heart from Doxorubicin-induced heart failure by reducing oxidative stress, inflammation, and apoptosis. It achieves this by activating the AMPK/Sirt1 pathway and inhibiting NF-κB signaling, thus preserving mitochondrial function.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Molecular Biology
Background:
- Heart failure (HF) is a critical stage of cardiovascular disease.
- Doxorubicin (DOX) chemotherapy can induce cardiotoxicity via oxidative stress, inflammation, and apoptosis.
- Ginkgetin (GK) shows potential cardioprotective effects, but its mechanisms are not fully understood.
Purpose of the Study:
- To investigate the protective effects of Ginkgetin (GK) against Doxorubicin (DOX)-induced heart failure.
- To elucidate the underlying mechanisms, focusing on mitochondrial function and key signaling pathways.
Main Methods:
- Utilized in vivo (mice) and in vitro (H9c2 cardiomyocytes) models of DOX-induced heart failure.
- Assessed cardiac function, myocardial injury, oxidative stress, inflammation, and apoptosis using various biochemical and histological techniques.
- Evaluated mitochondrial function and analyzed the AMPK/Sirt1/NF-κB signaling pathway.
Main Results:
- Ginkgetin (GK) significantly improved cardiac function and reduced myocardial injury markers and inflammatory cytokines in DOX-treated models.
- GK treatment restored mitochondrial structure and function, increased antioxidant capacity, and reduced apoptosis.
- GK upregulated AMPK and Sirt1, while inhibiting NF-κB activation, effects reversed by Compound C.
Conclusions:
- Ginkgetin (GK) demonstrates significant cardioprotective effects against Doxorubicin-induced heart failure.
- GK exerts its protective effects by activating the AMPK/Sirt1 pathway and inhibiting NF-κB signaling.
- These actions collectively mitigate oxidative stress, inflammation, apoptosis, and mitochondrial dysfunction, highlighting GK as a potential therapeutic agent.
Background:
Heart failure (HF) represents the terminal stage of many cardiovascular diseases. Doxorubicin (DOX) can induce HF through oxidative stress (OS), inflammation, and apoptosis. Ginkgetin (GK) has potential cardioprotective effects, but its underlying mechanisms remain unclear.
Aims:
To investigate of GK against DOX-induced HF and explored its mechanisms, focusing on mitochondrial function and related signaling pathways.
Study Design:
In vivo and in vitro experimental models.
Methods:
HF was induced by DOX in mice and H9c2 cardiomyocytes. Cardiac function, myocardial injury, OS, inflammation, and apoptosis were assessed using echocardiography, biochemical assays, enzyme-linked immunosorbent assay, histopathology, immunofluorescence, and Western blot. Mitochondrial function was evaluated via transmission electron microscopy, RT-qPCR, and Seahorse analysis. Compound C was applied to verify the involvement of the adenosine monophosphate-activated protein kinase (AMPK)/Sirt1/nuclear factor-κB (NF-κB) pathway.
Results:
GK markedly improved DOX-induced cardiac dysfunction and myocardial injury, reduced cardiac injury markers and inflammatory cytokines, and alleviated fibrosis, hypertrophy, apoptosis, and reactive oxygen species accumulation. GK restored superoxide dismutase activity, decreased malondialdehyde levels, increased glutathione and ATP, and preserved mitochondrial structure and respiratory function. GK upregulated AMPK and Sirt1, inhibited NF-κB activation, and regulated apoptosis-related proteins, whereas Compound C reversed these effects.
Conclusion:
GK protects against DOX-induced HF by activating AMPK/Sirt1 and inhibiting NF-κB signaling, thereby mitigating OS, inflammation, apoptosis, and mitochondrial dysfunction.
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