Identifying the cardioprotective mechanism of Danyu Tongmai Granules against myocardial infarction by targeted metabolomics combined with network pharmacology

Jing Cui; Yangyang Shi; Xueli Xu; Fei Zhao; Ji Zhang; Bo Wei

doi:10.1016/j.phymed.2021.153829

Identifying the cardioprotective mechanism of Danyu Tongmai Granules against myocardial infarction by targeted metabolomics combined with network pharmacology

Phytomedicine. 2022 Apr:98:153829. doi: 10.1016/j.phymed.2021.153829. Epub 2021 Oct 27.

Authors

Jing Cui¹, Yangyang Shi¹, Xueli Xu¹, Fei Zhao¹, Ji Zhang², Bo Wei³

Affiliations

¹ Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, No. 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
² Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China; Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou 450052, China.
³ Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, No. 100 Kexue Avenue, Zhengzhou, Henan 450001, China. Electronic address: weibozz101@163.com.

PMID: 35104768
DOI: 10.1016/j.phymed.2021.153829

Abstract

Background: Danyu Tongmai Granules (DY), the commercial Chinese medicine, was well-accepted cardiovascular protective actions in clinic. However, the mechanisms underlying the beneficial effects of DY on cardiovascular disease still need largely to be clarified.

Purpose: Therefore, this study was designed to explore potential mechanisms of DY in myocardial infarction (MI) by integrated strategy of metabolomics and network pharmacology.

Methods: Cardiomyocytes were subjected to H₂O₂ induced myocardial injury and rats were induced MI via isoproterenol (ISO) injection. The entire metabolic alterations in serum and heart tissues of experimental rats were profiled by UPLC-MS/MS. Based on the identified differential metabolites, the pathway analysis results were obtained and further validated using the network pharmacology approach.

Results: We found that DY exerted significant cardioprotective effects in vitro and in vivo, and ameliorated inflammatory cell infiltration and cardiomyocyte apoptosis induced by ISO. The metabolomics data suggested that DY mainly affected the amino acid metabolism (i.e., valine, leucine and isoleucine biosynthesis, arginine biosynthesis, phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, arginine biosynthesis, glycine, serine, as well as the alanine metabolism, aspartate and glutamate metabolism, etc.). Simultaneously, DY participated in the regulation of the biosynthesis of bile acids and biosynthesis of unsaturated fatty acids. Notably, DY significantly reduced the biosynthesis of valine, leucine and isoleucine to regulating the metabolism of branched chain amino acids (BCAAs) in infarcted myocardium, thus blocking the inflammation via inhibiting the expression of NLRP3 inflammasome in ISO-induced rats. The anti-inflammatory system of DY was further validated with the results of network pharmacology.

Conclusion: Our study, for the first time, confirmed that DY inhibited inflammation and further exerted significant anti-myocardial infarction effect. Additionally, our work further demonstrated that the myocardial protective effect of DY was contributed to the inhibition of the NLRP3 inflammasome activation by regulating BCAAs in infarcted myocardium using the comprehensive metabolomics, molecular biology and network analysis. Overall, our study gained new insights into the role of the relationship between the metabolic regulation of BCAAs and the NLRP3 inflammasome against MI.

Keywords: Branched chain amino acids; Metabolomics; Myocardial infarction; NLRP3; Network pharmacology.