基于代谢组学探讨鸡鸣散改善射血分数保留的心力衰竭的作用机制
[Mechanism of Jiming Powder in ameliorating heart failure with preserved ejection fraction based on metabolomics].
作者信息
Wei Xiao-Qi, Fan Xin-Yi, Pu Hai-Yin, Li Shuai, Tang Jia-Yang, Gao Kuo, Li Fang-He, Yu Xue, Guo Shu-Zhen
机构信息
School of Traditional Chinese Medicine, Beijing University of Chinese Medicine Beijing 100029, China.
出版信息
Zhongguo Zhong Yao Za Zhi. 2023 Sep;48(17):4747-4760. doi: 10.19540/j.cnki.cjcmm.20230510.702.
In this study, untargeted metabolomics was conducted using the liquid chromatography-tandem mass spectrometry(LC-MS/MS) technique to analyze the potential biomarkers in the plasma of mice with heart failure with preserved ejection fraction(HFpEF) induced by a high-fat diet(HFD) and nitric oxide synthase inhibitor(Nω-nitro-L-arginine methyl ester hydrochloride, L-NAME) and explore the pharmacological effects and mechanism of Jiming Powder in improving HFpEF. Male C57BL/6N mice aged eight weeks were randomly assigned to a control group, a model group, an empagliflozin(10 mg·kg(-1)·d(-1)) group, and high-and low-dose Jiming Powder(14.3 and 7.15 g·kg(-1)·d(-1)) groups. Mice in the control group were fed on a low-fat diet, and mice in the model group and groups with drug intervention were fed on a high-fat diet. All mice had free access to water, with water in the model group and Jiming Powder groups being supplemented with L-NAME(0.5 g·L~(-1)). Drugs were administered on the first day of modeling, and 15 weeks later, blood pressure and cardiac function of the mice in each group were measured. Heart tissues were collected for hematoxylin-eosin(HE) staining to observe pathological changes and Masson's staining to observe myocardial collagen deposition. Untargeted metabolomics analysis was performed on the plasma collected from mice in each group, and metabolic pathway analysis was conducted using MetaboAnalyst 5.0. The results showed that the blood pressure was significantly lower and the myocardial concentric hypertrophy and left ventricular diastolic dysfunction were significantly improved in both the high-dose and low-dose Jiming Powder groups as compared with those in the model group. HE and Masson staining showed that both high-dose and low-dose Jiming Powder significantly alleviated myocardial fibrosis. In the metabolomics experiment, 23 potential biomarkers were identified and eight strongly correlated metabolic pathways were enriched, including linoleic acid metabolism, histidine metabolism, alpha-linolenic acid metabolism, glycerophospholipid metabolism, purine metabolism, porphyrin and chlorophyll metabolism, arachidonic acid metabolism, and pyrimidine metabolism. The study confirmed the pharmacological effects of Jiming Powder in lowering blood pressure and ameliorating HFpEF and revealed the mechanism of Jiming Powder using the metabolomics technique, providing experimental evidence for the clinical application of Jiming Powder in treating HFpEF and a new perspective for advancing and developing TCM therapy for HFpEF.
在本研究中,采用液相色谱-串联质谱(LC-MS/MS)技术进行非靶向代谢组学分析,以分析高脂饮食(HFD)和一氧化氮合酶抑制剂(盐酸Nω-硝基-L-精氨酸甲酯,L-NAME)诱导的射血分数保留的心力衰竭(HFpEF)小鼠血浆中的潜在生物标志物,并探讨鸡鸣散改善HFpEF的药理作用及机制。将8周龄雄性C57BL/6N小鼠随机分为对照组、模型组、恩格列净(10 mg·kg⁻¹·d⁻¹)组以及高、低剂量鸡鸣散(14.3和7.15 g·kg⁻¹·d⁻¹)组。对照组小鼠给予低脂饮食,模型组及药物干预组小鼠给予高脂饮食。所有小鼠均可自由饮水,模型组和鸡鸣散组的饮水中添加L-NAME(0.5 g·L⁻¹)。造模第一天开始给药,15周后,测量各组小鼠的血压和心功能。采集心脏组织进行苏木精-伊红(HE)染色以观察病理变化,进行Masson染色以观察心肌胶原沉积。对各组小鼠采集的血浆进行非靶向代谢组学分析,并使用MetaboAnalyst 5.0进行代谢通路分析。结果显示,与模型组相比,高剂量和低剂量鸡鸣散组的血压均显著降低,心肌向心性肥厚和左心室舒张功能障碍均得到显著改善。HE和Masson染色显示,高剂量和低剂量鸡鸣散均能显著减轻心肌纤维化。在代谢组学实验中,鉴定出23种潜在生物标志物,富集了8条强相关代谢通路,包括亚油酸代谢、组氨酸代谢、α-亚麻酸代谢、甘油磷脂代谢、嘌呤代谢、卟啉和叶绿素代谢、花生四烯酸代谢以及嘧啶代谢。本研究证实了鸡鸣散在降低血压和改善HFpEF方面的药理作用,并利用代谢组学技术揭示了鸡鸣散的作用机制,为鸡鸣散治疗HFpEF的临床应用提供了实验依据,为推进和发展HFpEF的中医治疗提供了新的视角。