Bioinformatics study of the pharmacological mechanism of sodium-glucose co-transporter 2 inhibitors in type 2 diabetes mellitus and coronary heart disease based on network pharmacology.

Sodium-glucose co-transporter 2 inhibitors (SGLT2is) have consistently been shown to be beneficial in reducing the incidence rate of coronary heart disease (CHD) in diabetic patients. However, their specific pharmacological mechanisms are still unknown. Therefore, we intend to explore the mechanism of SGLT2is in patients with type 2 diabetes mellitus (T2DM) combined with CHD through a network pharmacological approach. Firstly, the Swiss Target Prediction and Drugbank databases were used to predict the targets of SGLT2is. The CHD dataset GSE113079 and T2DM dataset GSE118139 were downloaded from the gene expression omnibus database, and the differentially expressed genes (DEGs) were analyzed. Then, the predicted targets of SGLT2is intersected with the DEGs of the two diseases, and the results were used to construct the "drug-targeted-disease (D-T-D)" and protein-protein interaction networks. Gene Ontology functional analyses and Kyoto Encyclopedia of Genes and Genomes pathway were used for functional studies of target genes. Finally, molecular docking of SGLT2i with target proteins was performed using AutoDockTools software, and the docking results were verified by ELISA, RT-qPCR and western-blot experiments. Among the drug targets of SGLT2is and DEGs in T2DM and CHD, a total of 14 common gene targets exist, and these genes mainly affect the disease progression through the "chemical carcinogenesis-reactive oxygen species","apoptosis," and "chemical carcinogenesis-receptor activation" pathways. Through hub gene identification, we identified 11 hub genes from these 14 targets, of which epidermal growth factor receptor (EGFR) had the highest score. Molecular docking results showed that ertugliflozin had the strongest intermolecular binding to EGFR and that ertugliflozin improved the viability of high-glucose (HG)/high-lipid combined hypoxia-reoxygenation-injured (HG/HP†+†H/R) cardiomyocytes and inhibited EGFR expression in cardiomyocytes. Based on network pharmacology and bioinformatics analysis, our study elucidated that EGFR is the hub gene for T2DM combined with CHD myocardial injury. Molecular docking and cell experiments further confirmed that SGLT2i-ERTU improves HG/HP†+†H/R myocardial cell injury by targeting EGFR. Our study deepened the pharmacological mechanism of SGLT2is in the treatment of T2DM combined with CHD and provided a new perspective and therapeutic basis for future experimental research and healthcare.