Chen Yao, Li Lin, Hu Cunyu, Zhao Xin, Zhang Peng, Chang Yanxu, Shang Ye, Pang Yafen, Qian Weiqiang, Qiu Xianzhe, Zhang Hongxia, Zhang Deqin, Zhang Shukun, Li Yuhong
Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai, Tianjin 301617, China.
Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai, Tianjin 301617, China; Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai, Tianjin 301617, China.
Phytomedicine. 2022 Apr;98:153951. doi: 10.1016/j.phymed.2022.153951. Epub 2022 Jan 21.
Heart failure (HF) is a grave health concern, with high morbidity and mortality, calling for the urgent need for new and alternative pharmacotherapies. Lingguizhugan decoction (LD) is a classic Chinese formula clinically used to treat HF. However, the underlying mechanisms involved are not fully elucidated.
Based on that, this study aims to investigate the effects and underlying mechanisms of LD on HF.
After confirming the therapeutic benefits of LD in transverse aortic constriction (TAC)-induced HF mice, network pharmacology and transcriptomic analyzes were utilized to predict the potential molecular targets and pathways of LD treatment in failing hearts, which were evaluated at 3 and 9 w after TAC. UHPLC-QE-MS analysis was utilized to detect bioactive ingredients from LD and plasma of LD-treated rats.
Our results showed that LD markedly alleviated cardiac dysfunction via down-regulating CH-related genes and proteins expression in TAC mice. Significantly, cardiac hypertrophy signaling, including AKT and MAPKs signaling pathways, were identified, suggesting the pathways as likely regulatory targets for LD treatment. LD inhibited p38 and ERK phosphorylated expression levels, with the latter effect likely dependent on regulation of AMPK. Interestingly, LD exerted a dual modulatory role in the AKT-GSK3β/mTOR/P70S6K signaling pathway's regulation, which was characterized by stimulatory activity at 3 w and inhibitory effects at 9 w. Finally, 15 bioactive compounds detected from plasma were predicted as the potential regulators of the AKT-GSK3β/mTOR and MAPKs signaling pathways.
Our study shows LD's therapeutic efficacy in failing hearts, signifies LD as HF medication that acts dynamically by balancing AKT-GSK3β/mTOR/P70S6K and MAPKs pathways, and reveals possible bioactive compounds responsible for LD effects on HF.
心力衰竭（HF）是一个严重的健康问题，发病率和死亡率都很高，迫切需要新的替代药物疗法。苓桂术甘汤（LD）是临床上用于治疗HF的经典中药方剂。然而，其潜在机制尚未完全阐明。
基于此，本研究旨在探讨LD对HF的作用及其潜在机制。
在证实LD对横向主动脉缩窄（TAC）诱导的HF小鼠具有治疗效果后，利用网络药理学和转录组学分析预测LD治疗衰竭心脏的潜在分子靶点和途径，这些靶点和途径在TAC后3周和9周进行评估。利用超高效液相色谱-四极杆飞行时间质谱（UHPLC-QE-MS）分析检测LD中的生物活性成分以及LD处理大鼠血浆中的成分。
我们的结果表明，LD通过下调TAC小鼠中与CH相关的基因和蛋白质表达，显著减轻心脏功能障碍。值得注意的是，鉴定出了包括AKT和MAPKs信号通路在内的心脏肥大信号，表明这些通路可能是LD治疗的调控靶点。LD抑制p38和ERK的磷酸化表达水平，后者的作用可能依赖于AMPK的调节。有趣的是，LD在AKT-GSK3β/mTOR/P70S6K信号通路的调节中发挥双重调节作用，其特点是在3周时具有刺激活性，在9周时具有抑制作用。最后，从血浆中检测到的15种生物活性化合物被预测为AKT-GSK3β/mTOR和MAPKs信号通路的潜在调节剂。
我们的研究显示了LD对衰竭心脏的治疗效果，表明LD作为一种HF药物，通过平衡AKT-GSK3β/mTOR/P70S6K和MAPKs通路发挥动态作用，并揭示了可能导致LD对HF产生作用的生物活性化合物。
