Zhao Yan-Ting, Liu Yan-Ru, Yan Ya-Feng, Tang Zhi-Shu, Duan Jin-Ao, Yang Hui, Song Zhong-Xing, You Xue-Lian, Wang Ming-Geng
Shaanxi Collaborative Innovation Center Medicinal Resource Industrialization, Shaanxi University of Chinese Medicine, No. 1 Weiyang Road, Qindu District, Xianyang, 712083, People's Republic of China.
China Academy of Chinese Medical Sciences, No. 16, Nanxiao Street, Dongzhimen, Beijing, 100700, People's Republic of China.
Chin Med. 2023 Aug 19;18(1):103. doi: 10.1186/s13020-023-00812-x.
Fushenmu (Pini Radix in Poria, FSM) is a folk parasitic herb that has been mainly used for palpitation and amnesiain in traditional Chinese medicine (TCM). Recently, as an individual herb or a component of formulations, Fushenmu exhibits therapeutic potential for the treatment of cardiac arrhythmias. Yet, how specific targets or pathways of Fushenmu inhibit arrhythmia has not yet been reported.
Here, based on clinical functional genomics, metabolomics and molecular biologic technologies, a network construction strategy was adopted to identify FSM therapeutic targets and biomarkers that might explore its functions.
In this study, it was found that FSM recovered arrhythmia-associated heart failure in barium chloride (BaCl2) induced arrhythmic zebrafish embryos, as was evidenced by the shortened cardiac sinus venosus-bulbus arteriosus (SV-BA) distance, smaller cardiovascular bleeding areas, and reduced cardiomyocyte apoptosis. Moreover, analysis via ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-QTOF-ESI-MS/MS) components identification and network pharmacology prediction showed that 11 main active components of FSM acted on 33 candidate therapeutic targets. Metabolomic analysis also suggested that FSM could rescue 242 abnormal metabolites from arrhythmic zebrafish embryos. Further analysis based on the combination of target prediction and metabolomic results illustrated that FSM down-regulated Ryanodine Receptor 2 (RyR2) expressions, inhibited adrenaline and 3',5'-Cyclic AMP (cAMP) levels in a dose-dependent manner, which was confirmed by metabolites quantification and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assay.
In summary, this study revealed that FSM mitigated BaCl2 induced cardiac damage caused by arrhythmia by suppressing RyR2 expressions, decreasing adrenaline and cAMP through the adrenergic signalling pathway.
茯神木（茯苓寄生根，FSM）是一种民间寄生草药，在传统中医中主要用于治疗心悸和健忘。最近，茯神木作为单一草药或配方的成分，在治疗心律失常方面显示出治疗潜力。然而，茯神木抑制心律失常的具体靶点或途径尚未见报道。
在此，基于临床功能基因组学、代谢组学和分子生物学技术，采用网络构建策略来识别可能探索其功能的茯神木治疗靶点和生物标志物。
在本研究中，发现茯神木可恢复氯化钡（BaCl2）诱导的心律失常斑马鱼胚胎中与心律失常相关的心力衰竭，心脏静脉窦 - 动脉球（SV - BA）距离缩短、心血管出血面积减小以及心肌细胞凋亡减少均证明了这一点。此外，通过超高效液相色谱 - 串联质谱（UPLC - QTOF - ESI - MS/MS）成分鉴定和网络药理学预测分析表明，茯神木的11种主要活性成分作用于33个候选治疗靶点。代谢组学分析还表明，茯神木可以挽救心律失常斑马鱼胚胎中的242种异常代谢物。基于靶点预测和代谢组学结果的组合进一步分析表明，茯神木下调兰尼碱受体2（RyR2）表达，以剂量依赖性方式抑制肾上腺素和3',5'-环磷酸腺苷（cAMP）水平，代谢物定量和定量逆转录聚合酶链反应（qRT - PCR）分析证实了这一点。
总之，本研究表明茯神木通过抑制RyR2表达，通过肾上腺素能信号通路降低肾上腺素和cAMP，减轻了BaCl2诱导的心律失常引起的心脏损伤。
