| Coronary artery disease(CAD)has a high morbidity and mortality rate worldwide and is one of the main causes of death.CAD is a complex vascular and heart disease induced by many factors,among which hypertension,hyperlipidemia and diabetes are important pathogenic factors.Diabetes is a common metabolic disease.The number of diabetic patients is increasing worldwide and it has become an epidemic.Previous studies have shown that type 2 diabetes is an independent risk factor for patients with CAD.Compared with other risk factors,the pathological changes of patients with CAD and type 2 diabetes are more complicated.The two diseases promote each other and accelerate the course of the diseases.Metabolomics can detect multiple metabolites in body fluids at the same time and is a powerful research tool to discover potential biomarkers of diseases.Therefore,this study is based on the Chinese Han population of CAD and CAD patients with type 2 diabetes to carry out plasma metabolomics research to explore the differences in plasma metabolites and changes in related metabolic pathways between the two groups.And,the self-built LC-MS/MS detection method was used to further clarify the changes of the metabolites of different metabolic pathways of tryptophan in healthy people,patients with CAD and CAD combined with type 2 diabetes.Finally,in vitro human liver microsomes incubated tryptophan metabolism model to explore potential compounds that can affect tryptophan metabolism.The main research contents are as follows:First,we selected 1,018 patients with CAD and CAD combined with type 2 diabetes,and analyzed the plasma metabolomics between the two groups.The results of adjust analysis showed that 11 metabolites had statistical differences.Further pathway enrichment analysis revealed that tryptophan metabolism and arginine biosynthesis changed.In addition,we enrolled 551 patients with CAD,and CAD combined with type 2 diabetes from three centers.The plasma metabolome results showed that there were 32 metabolites with FDR<0.05,and pathway enriched analysis revealed changes in cysteine and methionine metabolism,tryptophan metabolism,histidine metabolism of linolenic acid metabolism,etc.In both the discovery and verification cohorts,it was found that tryptophan levels were significantly reduced in CAD with type 2 diabetes group.Secondly,based on the above findings,changes in plasma tryptophan metabolism pathways occur in CAD with type 2 diabetes.We further explored the changes of the metabolites of three different metabolic pathways of tryptophan in healthy people,patients with CAD,and CAD combined with type 2 diabetes.Compared with the healthy control group,the plasma tryptophan concentration,kynurenine and serotonin pathways in patients with CAD,and CAD with type 2 diabetes changed significantly.The IAA and IAA/TRP ratios of CAD with type 2 diabetes group were lower than those of patients with CAD.Finally,we used liver transcriptome data analysis and found that the key enzyme IDO1 of the kynurenine pathway is positively correlated with glycolytic gene expression,while the metabolic enzyme genes downstream of KYN are negatively correlated with HK1.The tryptophan metabolic enzyme gene was correlated with the expression of lipid-related genes.This further suggests the relationship between tryptophan metabolism and glucose metabolism lipid metabolism.In addition,we established an in vitro human liver microsome incubation tryptophan metabolism system,and found that resveratrol can inhibit IDO activity and reduce the metabolism of tryptophan to KYN,and it is dose-dependent.In summary,this study investigated the plasma metabonomics of patients with CAD and CAD combined with type 2 diabetes in the Chinese Han population,and found that the tryptophan metabolism pathways were different between the two groups.And further investigate the changes in the metabolites of the three metabolic pathways of tryptophan among different groups.At the same time,a system for the metabolism of tryptophan by human liver microsomes in vitro was established.This study provides a theoretical basis for discovering biomarkers and potential intervention targets in CAD with type 2 diabetes,and provides a reference for finding potential compounds that interfere with tryptophan metabolism. |
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