Mechanism Study For "Invigorating Qi And Promoting Blood Circulation" Effect On The Treatment Of Ischemic Heart Disease By The Drug Pairs,Astragalus Membranaceus And Salvia Miltiorrhiza

Ischemic heart disease(IHD)is a major disease affecting well-being of millions of human.According to traditional theory of Chinese medicine(CM),the basic pathogenesis of IHD is”Qi deficiency and blood stasis”.Consequently,"invigorating qi and promoting blood circulation"("IQ-PBC")is an effective strategy for treatment,which has been utilized in China for a long time and particularly effective for the treatment of "Qi Deficiency and Blood Stasis".However,systematic studies are warranted to clarify the scientific connotation of "invigorating qi"("IQ"),"promoting blood circulation"("PBC”),and "IQ-PBC".In this thesis,Astragalus Membranaceus(A.M.)and Salvia Miltiorrhiza(S.M.)were selected as representative research objects for IHD treatment to explore the scientific connotation for "IQ-PBC" effect of A.M.-S.M drug pairs.A series of research tools,such as transcriptomics,network modeling and analysis,were integrated to enhance the understanding from the molecular,cellular and systemic level.The main findings and contributions of this thesis are as following:1.Text mining revealed that A.M.(drug for invigorating qi,IQ-drug)and S.M.(drug for promoting blood circulation,PBC-drug)were the most commonly used TCM for IHD treatment.Thus,these two drugs were taken as the research objects.2.The cardioprotective effects of A.M.and its main active compounds were investigated and the relationship between energy metabolism and "IQ" effect of A.M.was elucidated.The extract of A.M.modulated energy metabolism in vivo by reducing serum and myocardial tissue concentrations of free fatty acid,pyruvic acid and lactic acid and increasing adenine nucleotides levels in myocardial tissue of myocardial infarction rats.Three main compounds,including astragaloside IV,calycosin and formononetin,were found to elevate ATP content,improve ATPase activity and influence PPAR signaling pathway related protein expression in vitro.These results showed that protective mechanism of A.M.against ischemic injury was possibly exerted by improving energy metabolism in cardiomyocytes through PPAR signaling pathway,indicating that energy metabolism improvement is contributing to "IQ" effect of A.M.3.The potential mechanism of "PBC" effect of S.M.was studied by network pharmacology.Ischemic heart disease(IHD)network,ischemic heart disease and hematological disorder(IHD-HD)network,and target network of S.M.were constructed and analyzed to study the mechanisms and scientific connotation of S.M.for treating IHD and IHD-HD.Several pathways play a regulatory role in therapeutic activity of S.M.,including the glucocorticoid receptor signaling,HMGB1 signaling,aryl hydrocarbon receptor signaling,VEGF Signaling pathways,and so on.These results suggested "PBC" effect of S.M.is closely related to the modulation of these pathways.4.Transcriptomics study was performed to study the mechanism of "IQ-PBC"effect of the representative compounds of the A.M.-S.M.drug pairs for treating IHD.The results showed that:1)Astragaloside IV,the representative compound of A.M.,executes its "IQ" effect by regulating several specific pathways,including Aldosterone Signaling in Epithelial Cells,Telomerase Signaling,Rac Signaling,NGF Signaling,Amyloid Processing,etc;2)Sodium Danshensu,the representative compound of S.M.,exerts its "PBC" effect also by adjusting several specific pathways,including IL-9 Signaling,Antioxidant Action of Vitamin C,Role of JAK family kinases in IL-6-type Cytokine Signaling,CTLA4 Signaling in Cytotoxic T Lymphocytes,Apoptosis Signaling,etc;3)These two representative compounds of A.M.-S.M.drug pairs shows the "IQ-PBC" effect by modulating several specific pathways,including Circadian Rhythm Signaling,Protein Kinase A Signaling,CDK5 Signaling,TNFR2 Signaling,fMLP Signaling in Neutrophils,etc.