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A Doxorubicin-induced Cardiomyopathy Model in Adult Zebrafish
Published on: June 7, 2018
Engeletin alleviates doxorubicin-induced cardiotoxicity via the AMPK pathway in mice
Xin Chen1,2,3, Xing Zhong4, Dan Luo1,2,3
1Cardiovascular Disease Center, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, Hubei, China.
Background:
The extensively employed antineoplastic drug doxorubicin (DOX) is constrained in clinical utilization on account of its severe cardiotoxicity, and there persists a dearth of protective agents against doxorubicin-induced cardiotoxicity (DIC). Engeletin (ENG) is a natural product endowed with multiple biological activities and has manifested significant protective effects in various diseases. This study purports to explore the protective effects of ENG in DIC and elucidate the underlying mechanisms.
Methods:
H9C2 cardiomyocytes and C57BL/6 mice were used to establish in vitro and in vivo models of DIC, and ENG was used for treatment. Cardiac function and structural changes in the mice were assessed by ultrasound, pathological section staining and transmission electron microscopy. Western blotting, Real-Time Quantitative PCR, immunofluorescence staining, enzyme-linked immunosorbent assay (ELISA), serum biochemical detection, TUNEL staining, dihydroethidium (DHE) assay, and flow cytometry were employed to evaluate apoptosis, autophagy, oxidative stress, inflammation, mitochondrial damage, ANP and BNP both in vitro and in vivo. An AMPK inhibitor Compound C was utilized to validate the effect of ENG on the AMPK pathway.
Results:
DOX diminished cardiac function and induced fibrosis in mice, resulting in significant cell apoptosis, oxidative stress, inflammation, autophagy dysregulation, and mitochondrial damage both in vitro and in vivo. Following ENG treatment, these conditions can be markedly ameliorated, especially in mitigating myocardial cell apoptosis, autophagy, and oxidative stress responses. It has been found that this effect is realized through the activation of the AMPK pathway. Moreover, utilization of an AMPK inhibitor CC impeded the protective effect of ENG on DIC.
Conclusion:
ENG has mitigated DIC through the activation of the AMPK pathway, thereby rendering it a potential drug for the prevention and treatment of DIC.
Insights
Engeletin (ENG) protects against doxorubicin-induced cardiotoxicity (DIC) by activating the AMPK pathway. This natural product ameliorates cardiac dysfunction and cellular damage, offering a potential therapeutic strategy for DIC.
Area of Science:
- Cardiology
- Pharmacology
- Biochemistry
Background:
- Doxorubicin (DOX) is a vital anticancer drug, but its clinical use is limited by severe cardiotoxicity.
- Doxorubicin-induced cardiotoxicity (DIC) lacks effective protective agents.
- Engeletin (ENG), a natural product, exhibits diverse biological activities and potential therapeutic benefits.
Purpose of the Study:
- To investigate the protective effects of Engeletin (ENG) against doxorubicin-induced cardiotoxicity (DIC).
- To elucidate the underlying molecular mechanisms of ENG's cardioprotective action in DIC.
Main Methods:
- Established in vitro (H9C2 cardiomyocytes) and in vivo (C57BL/6 mice) models of DIC.
- Assessed cardiac function and structure using echocardiography, histology, and electron microscopy.
- Utilized molecular biology techniques (Western blotting, qPCR, ELISA, flow cytometry) to evaluate apoptosis, autophagy, oxidative stress, inflammation, and mitochondrial damage. Investigated the role of the AMPK pathway using an inhibitor.
Main Results:
- Doxorubicin treatment impaired cardiac function, induced fibrosis, apoptosis, oxidative stress, inflammation, autophagy dysregulation, and mitochondrial damage.
- ENG treatment significantly ameliorated these DOX-induced detrimental effects, particularly reducing myocardial apoptosis, autophagy, and oxidative stress.
- ENG's protective effects were mediated through the activation of the AMPK pathway, as confirmed by experiments using an AMPK inhibitor.
Conclusions:
- Engeletin (ENG) demonstrates significant cardioprotective effects against doxorubicin-induced cardiotoxicity (DIC).
- ENG exerts its protective effects by activating the AMPK pathway.
- ENG represents a promising therapeutic candidate for the prevention and treatment of DIC.
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