Pharmacological analysis of Empagliflozin: Acting through the CaMKII pathway in type 2 diabetes and acute cardiovascular events

Abstract

Background Type 2 diabetes mellitus is a high-risk factor for acute cardiovascular events. Some reports show that Empagliflozin has a protective effect on cardiovascular events and diabetes mellitus, and Empagliflozin can act on the CaMKII pathway. However, the specific gene of action is not precise. Therefore, this study investigated the target genes of Empagliflozin by integrated gene analysis and molecular docking method to provide a theoretical basis for further elucidating the mechanism of action of Empagliflozin. Method In this study, we obtained 12 datasets from GEO, divided into experimental and validation groups, with a total of 376 samples. We then integrated CaMKII pathway-related genes from OMIM, NCBI, and genecards databases. We then intersected them with the differential genes we obtained to obtain 5 common genes and performed functional enrichment analysis. We then performed group comparisons in the validation set, and we obtained 2 clinically significant genes. Then we performed group comparison in the validation set, and we obtained 2 clinically significant genes, followed by molecular docking analysis with pymol, autodock software. We obtained molecular docking models for the 2 genes. Conclusion In this study, we obtained CaMK2G and PPP1CA, genes associated with the CaMKII pathway and type 2 diabetes and acute cardiovascular events, by integrative gene analysis and validated their expression in the relevant dataset. We also derived that Empagliflozin acts on amino acid TRP-125 of CaMK2G gene and GLN-249 ASP-210 ASP-208 of PPP1CA through CaMKII pathway, thus acting on type 2 diabetes and acute cardiovascular events by molecular docking technique. Background Patients with type 2 diabetes are at increased risk of developing cardiovascular disease [1]. Empagliflozin may reduce mortality from cardiovascular events by affecting hemodynamic effects [2]. It has been shown that empagliflozin contributes to cardiovascular disease by acting on the CaMKII pathway, decreasing its activity and reducing CaMKII pathway-dependent calcium efflux [3]. However, the genes in which Empagliflozin acts on the CAMKII pathway have not been reported. The search for markers of Empagliflozin at the transcriptome level is essential to understand the mechanism of action of Empagliflozin. Therefore, this study was conducted to investigate and demonstrate the target genes of Empagliflozin by integrating bioinformatics techniques and molecular docking techniques. Method Data acquisition and processing In this study, 12 datasets with a total of 376 samples(The specific information such as the origin of the tissue is shown in Table 1) were obtained from the Gene Expression Omnibus (GEO database, https://www.ncbi.nlm.nih.gov/geo/) [4], and differential gene analysis was performed using R language to draw heat maps and volcano maps. In this study, the data from the GEO database were screened. The screening criteria were as follows: 1. search with the keywords "type 2 diabetes" and "acute heart disease." 2. restrict the entry type to series 3. restrict the study type to expression analysis of arrays. 4. the data retrieved had controlled. 5. the data retrieved had genetic samples. 6. the organisms were restricted to Homo sapiens. Exclusion criteria were as follows: 1. The data retrieved had drug treatment or other confounding factors in the experimental group. 2. The data retrieved did not have genetic samples. 3. The data obtained from the survey did not have grouping information. 4. The data obtained by probing did not have grouping information. 5. The source of the samples was not Homo sapiens.