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Published on: July 10, 2019
Astragaloside IV intervenes multi-regulatory cell death forms against doxorubicin-induced cardiotoxicity by
Yichen Hu1, Jingzhi Yu2, Wanxian He3
1Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University School of Pharmaceutical Science, Nanchang 330006, China; Jiangxi Provincial Key Laboratory of Periodontology, the Second Affiliated Hospital of Nanchang University, Nanchang 330006, China.
Abstract:
The clinical use of doxorubicin has been severely limited by doxorubicin-induced cardiotoxicity (DIC). Its mechanism is extremely complex and involves reactive oxygen species overgeneration, DNA damage, and aberrant inflammatory activity, which also involves multi-regulatory cell death mechanisms, including apoptosis, autophagy, and pyroptosis. These mechanisms overlap and crosstalk, resulting in the poor intervention of DIC injury. Astragaloside IV (Ast) has polybioactivity and mitigates DIC damage; however, the underlying mechanisms remain unknown. This study aimed to investigate whether Ast pretreatment (Ast-pre) could protect the myocardium against DIC damage and the underlying mechanisms. In particular, the relationship between Ast-pre, AMPKα2 activity, autophagy, apoptosis, and pyroptosis was explored. Firstly, DIC injury models were established using neonatal rat cardiomyocytes (NRCMs) and mice. And then the effects of adaptive autophagy, anti-pyroptosis and anti-apoptosis of Ast-pre were detected using multi-relevant indexes in NRCMs. Further, how does Ast-pre in AMPKα2 phosphorylation was explored. Finally, these results were validated by DIC injury in mice. Ast-pre, similar to disulfiram (pyroptosis inhibitor), effectively alleviated the inflammatory response, inhibited oxidative and energy stress, prevented mitochondrial dysfunction, and protected the myocardium resisting DIC damage, as demonstrated using multi-indexes. The protection of Ast-pre to DIC damage was almostly canceled by paclitaxel (pyroptosis inducer), 3-methyladenine (autophagy inhibitor), and pAD/AMPKα2-shRNA or compound C (AMPK inhibitor) to varying degrees. In conclusion, Ast-pre could upregulate and activate AMPKα2, enhance adaptive autophagy, and improve energy metabolism and mitochondrial function, thereby alleviate DIC-induced pyroptosis and apoptosis in NRCMs and mice.
Insights
Astragaloside IV pretreatment protects the heart from doxorubicin-induced cardiotoxicity (DIC) by activating AMPKα2, promoting autophagy, and reducing apoptosis and pyroptosis. This offers a potential therapeutic strategy against DIC.
Area of Science:
- Cardiology
- Pharmacology
- Molecular Biology
Background:
- Doxorubicin-induced cardiotoxicity (DIC) severely limits clinical applications due to complex mechanisms involving oxidative stress, DNA damage, and cell death pathways.
- Existing interventions for DIC are inadequate due to the intricate interplay between apoptosis, autophagy, and pyroptosis.
- Astragaloside IV (Ast) exhibits protective effects, but its mechanisms against DIC remain unclear.
Purpose of the Study:
- To investigate the protective effects of Astragaloside IV pretreatment (Ast-pre) against doxorubicin-induced cardiotoxicity (DIC).
- To elucidate the underlying mechanisms, focusing on the relationship between Ast-pre, AMPKα2 activity, autophagy, apoptosis, and pyroptosis.
Main Methods:
- Established DIC injury models using neonatal rat cardiomyocytes (NRCMs) and mice.
- Assessed the effects of Ast-pre on autophagy, pyroptosis, and apoptosis using relevant molecular and cellular indexes in NRCMs.
- Investigated the role of Ast-pre in AMPKα2 phosphorylation and validated findings in a mouse model of DIC.
Main Results:
- Ast-pre significantly alleviated inflammatory responses, oxidative and energy stress, and mitochondrial dysfunction in DIC models, mirroring the effects of a pyroptosis inhibitor.
- The protective effects of Ast-pre were partially reversed by pyroptosis inducers, autophagy inhibitors, and AMPK inhibitors, indicating the involvement of these pathways.
- Ast-pre upregulated and activated AMPKα2, enhanced adaptive autophagy, and improved energy metabolism and mitochondrial function.
Conclusions:
- Astragaloside IV pretreatment protects the myocardium against doxorubicin-induced cardiotoxicity.
- This protection is mediated by the activation of AMPKα2, which enhances adaptive autophagy and improves mitochondrial function.
- Ast-pre effectively alleviates DIC-induced pyroptosis and apoptosis, presenting a promising therapeutic avenue.
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