Jiangxi 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.
Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University School of Pharmaceutical Science, Nanchang 330006, China.
Int Immunopharmacol. 2024 Dec 5;142(Pt A):113078. doi: 10.1016/j.intimp.2024.113078. Epub 2024 Sep 4.
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.
阿霉素的临床应用受到阿霉素诱导的心脏毒性（DIC）的严重限制。其机制极其复杂，涉及活性氧过度生成、DNA 损伤和异常炎症活性，还涉及多种调节细胞死亡机制，包括细胞凋亡、自噬和细胞焦亡。这些机制相互重叠和相互作用，导致 DIC 损伤的干预效果不佳。黄芪甲苷（Ast）具有多生物活性，可减轻 DIC 损伤；然而，其潜在机制尚不清楚。本研究旨在探讨 Ast 预处理（Ast-pre）是否可以保护心肌免受 DIC 损伤及其潜在机制。特别是，探讨了 Ast-pre、AMPKα2 活性、自噬、凋亡和细胞焦亡之间的关系。首先，使用新生大鼠心肌细胞（NRCMs）和小鼠建立 DIC 损伤模型。然后，使用 NRCMs 中的多个相关指标检测 Ast-pre 的适应性自噬、抗细胞焦亡和抗细胞凋亡作用。进一步探讨 Ast-pre 对 AMPKα2 磷酸化的影响。最后，通过 DIC 损伤在小鼠中验证这些结果。Ast-pre 与双硫仑（细胞焦亡抑制剂）相似，通过多种指标有效缓解炎症反应，抑制氧化和能量应激，防止线粒体功能障碍，保护心肌抵抗 DIC 损伤。Ast-pre 对 DIC 损伤的保护作用几乎被紫杉醇（细胞焦亡诱导剂）、3-甲基腺嘌呤（自噬抑制剂）、pAD/AMPKα2-shRNA 或化合物 C（AMPK 抑制剂）不同程度地取消。总之，Ast-pre 可以上调和激活 AMPKα2，增强适应性自噬，改善能量代谢和线粒体功能，从而减轻 NRCMs 和小鼠中 DIC 诱导的细胞焦亡和细胞凋亡。
