Hai Zhang1, Yahong Zhao2, Zhengxiang Xia1, Hongli Du3, Yue Gao4, Dan Xue2, Zhenyu Zhu5, Yifeng Chai6. 1. Department of Pharmacy, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai 201204, China. 2. Department of Chinese Materia Medica, Central Research Institute, Shanghai Pharmaceuticals Holding Co.Ltd., Shanghai 201203, China. 3. Department of Pharmacy, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200433, China. 4. School of Pharmacy, Second Military Medical University, Shanghai 200433, China. 5. School of Pharmacy, Second Military Medical University, Shanghai 200433, China. Electronic address: zzyzyfzhu@163.com. 6. School of Pharmacy, Second Military Medical University, Shanghai 200433, China. Electronic address: yfchai@smmu.edu.cn.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Myocardial ischemia-reperfusion (I/R) injury is a serious injury that is resulted from the recovery of blood supply after myocardial ischemia. Yangxinshi tablet is a compound Chinese herbal preparation and often used to alleviate the myocardial ischemia in clinical, but its protective mechanism of anti-myocardial ischemia reperfusion injury remains unclear. The objective of this study was to evaluate the anti-I/R injury effect of Yangxinshi tablet on a myocardial I/R rat model and to identify serum biomarker metabolites associated with I/R based on ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-QTOF/MS) metabolomic method, and explore the metabolic mechanism of anti-I/R injury of Yangxinshi tablet. MATERIALS AND METHODS: Unsupervised principle component analysis highlighted significant differences in the metabolome of the myocardial I/R, healthy control and drug-treated rats. Partial least squares-discriminant analysis revealed 25 metabolites as the most potential biomarker metabolites discriminating the myocardial I/R rats and control rats. Most of the metabolites were primarily involved in oxidative stress, energy metabolism, fatty acid metabolism, amino acid metabolism. These metabolites were validated by assessing the efficacy after intragastric administration of Yangxinshit ablet to the myocardial I/R rat model. RESULTS: Based on metabolomic results, the action mechanism of anti-I/R injury of Yangxinshi tablet was concluded as follows: (1) enhance the ability of scavenging free radicals and reactive oxygen species in vivo; (2) provide energy for myocardium via accelerating the intracellular carnitine transportion to accelerate the oxidation of fatty acid and (3) attenuate ceramide to reduce cardiomyocyte apoptosis. CONCLUSIONS: Yangxinshi tablet has cardio-protection effects on I/R rats via regulation of multiple metabolic pathways involving in oxidative stress, energy metabolism, fatty acid, and amino acid metabolisms. This study will be meaningful for its clinical application and valuable for further exploring the action mechanism of Yangxinshi tablet.
ETHNOPHARMACOLOGICAL RELEVANCE: Myocardial ischemia-reperfusion (I/R) injury is a serious injury that is resulted from the recovery of blood supply after myocardial ischemia. Yangxinshi tablet is a compound Chinese herbal preparation and often used to alleviate the myocardial ischemia in clinical, but its protective mechanism of anti-myocardial ischemia reperfusion injury remains unclear. The objective of this study was to evaluate the anti-I/R injury effect of Yangxinshi tablet on a myocardial I/R rat model and to identify serum biomarker metabolites associated with I/R based on ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-QTOF/MS) metabolomic method, and explore the metabolic mechanism of anti-I/R injury of Yangxinshi tablet. MATERIALS AND METHODS: Unsupervised principle component analysis highlighted significant differences in the metabolome of the myocardial I/R, healthy control and drug-treated rats. Partial least squares-discriminant analysis revealed 25 metabolites as the most potential biomarker metabolites discriminating the myocardial I/R rats and control rats. Most of the metabolites were primarily involved in oxidative stress, energy metabolism, fatty acid metabolism, amino acid metabolism. These metabolites were validated by assessing the efficacy after intragastric administration of Yangxinshit ablet to the myocardial I/R rat model. RESULTS: Based on metabolomic results, the action mechanism of anti-I/R injury of Yangxinshi tablet was concluded as follows: (1) enhance the ability of scavenging free radicals and reactive oxygen species in vivo; (2) provide energy for myocardium via accelerating the intracellular carnitine transportion to accelerate the oxidation of fatty acid and (3) attenuate ceramide to reduce cardiomyocyte apoptosis. CONCLUSIONS: Yangxinshi tablet has cardio-protection effects on I/R rats via regulation of multiple metabolic pathways involving in oxidative stress, energy metabolism, fatty acid, and amino acid metabolisms. This study will be meaningful for its clinical application and valuable for further exploring the action mechanism of Yangxinshi tablet.