基于代谢组学探究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：魏小棋 范昕怡 普海崟 李帅 唐家杨 高阔 李芳赫 于雪 郭淑贞 WEI Xiao-qi;FAN Xin-yi;PU Hai-yin;LI Shuai;TANG Jia-yang;GAO Kuo;LI Fang-he;YU Xue;GUO Shu-zhen(School of Traditional Chinese Medicine,Beijing University of Chinese Medicine,Beijing 100029,China)

机构地区：[1]北京中医药大学中医学院,北京100029

出　　处：《中国中药杂志》2023年第17期4747-4760,共14页China Journal of Chinese Materia Medica

基　　金：国家中医药管理局青年岐黄学者支持项目。

摘　　要：该研究采用液相色谱-串联质谱(LC-MS/MS)技术,进行非靶向代谢组学研究,分析了鸡鸣散干预高脂饮食(high-fat diet,HFD)和一氧化氮合成酶抑制剂(Nω-nitro-L-arginine methyl ester hydrochloride,L-NAME)诱导的射血分数保留的心力衰竭(heart failure with preserved ejection fraction,HFpEF)小鼠血浆中的潜在生物标志物,探究鸡鸣散改善HFpEF的药效和作用机制。随机将8周龄雄性C57BL/6N小鼠分为对照组、模型组、恩格列净组(10 mg·kg^(-1)·d^(-1))、鸡鸣散高剂量组(14.3 g·kg^(-1)·d^(-1))和鸡鸣散低剂量组(7.15 g·kg^(-1)·d^(-1)),对照组予以低脂饲料,模型组和各给药组予以高脂饲料,各组小鼠均自由饮水,模型组和给药组的小鼠饮水中加入一氧化氮合酶抑制剂(0.5 g·L^(-1)),从造模第1天开始给药,15周后检测各组小鼠血压和心功能,取小鼠心脏进行苏木精-伊红(hematoxylin-eosin,HE)染色观察病理改变,Masson染色检测各组小鼠心肌胶原纤维沉积;取小鼠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,鸡鸣散高、低剂量组血压显著下降,心肌向心性肥厚和左心室舒张功能障碍明显改善;HE和Masson染色显示,鸡鸣散高、低剂量组可显著改善心肌纤维化;代谢组学共筛选出23个血浆中的潜在生物标志物,分析出8条关联性较强的代谢通路,包括亚油酸代谢(linoleic acid metabolism)、组氨酸代谢(histidine metabolism)、α-亚麻酸代谢(alpha-linolenic acid metabolism)、甘油磷脂代谢(glyce-rophospholipid metabolism)、嘌呤代谢(purine metabolism)、卟啉与叶绿素代谢(porphyrin and chlorophyll metabolism)、花生四烯酸代谢(arachidonic acid metabolism)、嘧啶代谢(pyrimidine metabolism)。该研究明确了鸡鸣散具有降低血压和改善HFpEF的药效,并利用代谢组学技术揭示了鸡鸣散发挥药效的机制,为鸡鸣散在心力衰竭治疗中的临床运用提供了实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,glyce

关 键 词：鸡鸣散 高血压 肥胖 代谢组学 射血分数保留的心力衰竭 

分 类 号：R285.5[医药卫生—中药学]