Metabolic pathways involved in Xin-Ke-Shu protecting against myocardial infarction in rats using ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry

Abstract

Xin-Ke-Shu (XKS) is a patent drug used for coronary heart diseases in China. This study evaluated the protective effect of XKS against isoproterenol (ISO)-induced myocardial infarction (MI). For its underlying mechanism in rats with MI, a metabonomic approach was developed using ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC/QTOF-MS). Plasma metabolites were profiled in MI rats, pretreated orally with or without XKS. Two genres of metabolic biomarkers were used to elucidate the pharmacological action of XKS: pathological biomarkers and pharmaco biomarkers. Fifteen metabolites significantly varying between MI rats and normal rats were characterized as potential pathological biomarkers related to MI, including L-acetylcarnitine (1), L-isoleucyl-L-proline (2), tyramine (3), isobutyryl-L-carnitine (4), phytosphingosine (5), sphinganine (6), L-palmitoylcarnitine (7), lysoPC(18:0) (8), uric acid (9), L-tryptophan (10), lysoPC(18:2) (11), lysoPC(16:0) (12), docosahexaenoic acid (13), arachidonic acid (14) and linoleic acid (15). Among them, eight (1-6, 9 and 10) were first reported as pathological biomarkers related to ISO-induced MI, which mainly involved into fatty acid β-oxidation pathway, sphingolipid metabolism, proteolysis, tryptophan metabolism and purine metabolism. The metabolites significantly varying between MI rats with and without XKS pretreatment were considered as pharmaco biomarkers. A total of 17 pharmaco biomarkers were recognized, including 15 pathological biomarkers (1-15), hexanoylcarnitine (16) and tetradecanoylcarnitine (17). The results suggested that pretreatment of XKS protected metabolic perturbations in rats with MI, major via lipid pathways, amino acid metabolism and purine metabolism, which also provided a promising approach for evaluating the pharmacodynamics and mechanism of traditional Chinese medicines (TCM) formulas.

Keywords: Metabolic pathways; Myocardial infarction; Pharmacological action; Plasma metabonomics; Xin-Ke-Shu.