萨库比特利/缬沙坦通过调节 AMPKα-mTORC1 信号通路,减轻多柔比星诱导的心脏毒性小鼠的心肌炎症、纤维化和细胞凋亡,并促进自噬。

IF 3.5 2区 生物学 Q3 CELL BIOLOGY
Feng Hu, Senbo Yan, Li Lin, Xiaoxia Qiu, Xinghe Lin, Weiwei Wang
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引用次数: 0

摘要

本研究旨在探讨沙库比曲利/缬沙坦(Sac/Val)对多柔比星(DOX)诱导的心肌病小鼠的潜在心脏保护作用,多柔比星是与DOX相关的癌症治疗相关心脏功能障碍(CTRCD)的常见表现形式。32只小鼠被平均分为4组:对照组、DOX组(总剂量为24毫克/千克)、Sac/Val组(80毫克/千克)和Sac/Val + DOX组(Sac/Val在多柔比星给药前7天开始给药)。新生大鼠心室肌细胞在体外暴露于 5 µM DOX 6 小时,以模拟体内条件。实验采用了多种技术来研究心脏炎症、纤维化、细胞凋亡和自噬,包括 Western 印迹、实时定量 PCR(RT-qPCR)、免疫组化和荧光。DOX诱导的心脏毒性小鼠表现出收缩和舒张功能受损,心脏炎症、纤维化、心肌细胞肥大、细胞凋亡和自噬抑制水平升高。使用 Sac/Val 治疗可部分逆转这些影响。与对照组相比,Dox 诱导的心肌病组心肌组织中 NLRP3、caspase-1、胶原 I、Bax、裂解的 caspase-3 和 P62 的蛋白表达量显著增加,而 Bcl-2 和 LC3-II 的蛋白表达量则显著减少。通过调节 AMPKα-mTORC1 信号通路和抑制氧化应激,服用 Sac/Val 有可能部分逆转 DOX 诱导的心脏毒性小鼠心肌中蛋白质表达的改变。此外,Sac/Val 治疗可减轻 DOX 诱导的细胞凋亡和对原代心肌细胞自噬的抑制。在预处理小鼠模型中,Sac/Val 似乎对 DOX 诱导的心脏毒性有保护作用。这些发现可能是由于 Sac/Val 通过调节 AMPKα-mTORC1 信号通路,具有抗炎、抗氧化、抗凋亡和去自噬的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Sacubitril/valsartan attenuated myocardial inflammation, fibrosis, apoptosis and promoted autophagy in doxorubicin-induced cardiotoxicity mice via regulating the AMPKα-mTORC1 signaling pathway.

This study aimed to investigate the potential cardioprotective effects of sacubitril/valsartan (Sac/Val) in mice with doxorubicin (DOX)-induced cardiomyopathy, a common manifestation of cancer therapy-related cardiac dysfunction (CTRCD) associated with DOX. A total of thirty-two mice were equally classified into 4 groups: control group, DOX (total 24 mg/kg), Sac/Val (80 mg/kg), and Sac/Val + DOX (Sac/Val was given from seven days before doxorubicin administration). Neonatal rat ventricular myocytes was exposed to 5 µM of DOX for 6 h in vitro to mimic the in vivo conditions. A variety of techniques were used to investigate cardiac inflammation, fibrosis, apoptosis, and autophagy, including western blot, real-time quantitative PCR (RT-qPCR), immunohistochemistry, and fluorescence. Mice with DOX-induced cardiotoxicity displayed impaired systolic and diastolic function, characterized by elevated levels of cardiac inflammation, fibrosis, cardiomyocyte hypertrophy, apoptosis, and autophagy inhibition in the heart. Treatment with Sac/Val partially reversed these effects. In comparison to the control group, the protein expression of NLRP3, caspase-1, collagen I, Bax, cleaved caspase-3, and P62 were significantly increased, while the protein expression of Bcl-2 and LC3-II were significantly decreased in the myocardial tissues of the Dox-induced cardiomyopathy group. The administration of Sac/Val demonstrated the potential to partially reverse alterations in protein expression within the myocardium of mice with DOX-induced cardiotoxicity by modulating the AMPKα-mTORC1 signaling pathway and suppressing oxidative stress. Additionally, Sac/Val treatment may mitigate Dox-induced apoptosis and inhibition of autophagy in primary cardiomyocytes. Sac/Val seems to be cardioprotective against DOX-induced cardiotoxicity in the pre-treatment mice model. These findings could be attributed to the anti-inflammatory, antioxidant, anti-apoptotic, and de-autophagy effects of Sac/Val through regulation of the AMPKα-mTORC1 signaling pathway.

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来源期刊
Molecular and Cellular Biochemistry
Molecular and Cellular Biochemistry 生物-细胞生物学
CiteScore
8.30
自引率
2.30%
发文量
293
审稿时长
1.7 months
期刊介绍: Molecular and Cellular Biochemistry: An International Journal for Chemical Biology in Health and Disease publishes original research papers and short communications in all areas of the biochemical sciences, emphasizing novel findings relevant to the biochemical basis of cellular function and disease processes, as well as the mechanics of action of hormones and chemical agents. Coverage includes membrane transport, receptor mechanism, immune response, secretory processes, and cytoskeletal function, as well as biochemical structure-function relationships in the cell. In addition to the reports of original research, the journal publishes state of the art reviews. Specific subjects covered by Molecular and Cellular Biochemistry include cellular metabolism, cellular pathophysiology, enzymology, ion transport, lipid biochemistry, membrane biochemistry, molecular biology, nuclear structure and function, and protein chemistry.
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