Hu Feng, Yan Senbo, Lin Li, Qiu Xiaoxia, Lin Xinghe, Wang Weiwei
Department of Cardiology, Fujian Medical University Union Hospital, Fujian Cardiovascular Medical Center, Fujian Institute of Coronary Artery Disease, Fujian Cardiovascular Research Center, Fuzhou, 350001, People's Republic of China.
Mol Cell Biochem. 2025 Mar;480(3):1891-1908. doi: 10.1007/s11010-024-05117-7. Epub 2024 Sep 20.
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.
本研究旨在探讨沙库巴曲缬沙坦（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，多柔比星诱导的心肌病是与DOX相关的癌症治疗相关心脏功能障碍（CTRCD）的常见表现。总共32只小鼠被平均分为4组：对照组、DOX组（共24mg/kg）、Sac/Val组（80mg/kg）和Sac/Val + DOX组（在给予多柔比星前7天开始给予Sac/Val）。将新生大鼠心室肌细胞在体外暴露于5µM的DOX中6小时以模拟体内情况。使用了多种技术来研究心脏炎症、纤维化、细胞凋亡和自噬，包括蛋白质免疫印迹法、实时定量PCR（RT-qPCR）、免疫组织化学和荧光法。DOX诱导的心脏毒性小鼠表现出收缩和舒张功能受损，其特征是心脏炎症水平升高、纤维化、心肌细胞肥大、细胞凋亡和心脏自噬抑制。Sac/Val治疗部分逆转了这些作用。与对照组相比，在DOX诱导的心肌病组的心肌组织中，NLRP3、半胱天冬酶-1、胶原蛋白I、Bax、裂解的半胱天冬酶-3和P62的蛋白表达显著增加，而Bcl-2和LC3-II的蛋白表达显著降低。给予Sac/Val显示出通过调节AMPKα-mTORC1信号通路和抑制氧化应激，部分逆转DOX诱导的心脏毒性小鼠心肌中蛋白表达改变的潜力。此外，Sac/Val治疗可能减轻DOX诱导的原代心肌细胞凋亡和自噬抑制。在预处理小鼠模型中，Sac/Val似乎对DOX诱导的心脏毒性具有心脏保护作用。这些发现可能归因于Sac/Val通过调节AMPKα-mTORC1信号通路产生的抗炎、抗氧化、抗凋亡和去自噬作用。
