Astragaloside IV intervenes multi-regulatory cell death forms against doxorubicin-induced cardiotoxicity by regulating AMPKα2 pathway.
Int Immunopharmacol
; 142(Pt A): 113078, 2024 Dec 05.
Article
en En
| MEDLINE
| ID: mdl-39236461
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Saponinas
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Triterpenos
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Transducción de Señal
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Doxorrubicina
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Miocitos Cardíacos
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Proteínas Quinasas Activadas por AMP
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Cardiotoxicidad
Límite:
Animals
Idioma:
En
Revista:
Int Immunopharmacol
Asunto de la revista:
ALERGIA E IMUNOLOGIA
/
FARMACOLOGIA
Año:
2024
Tipo del documento:
Article
País de afiliación:
China
Pais de publicación:
Países Bajos