A Bioinformatics Investigation into the Pharmacological Mechanisms of Sodium-Glucose Co-transporter 2 Inhibitors on Diabetes Mellitus and Heart Failure based on Network Pharmacology

Abstract BackgroundDiabetes mellitus (DM) is a major risk factor for the development of heart failure (HF). Sodium-glucose co-transporter 2 (SGLT2) inhibitors have been demonstrated consistent benefits in the reduction of hospitalization for HF in patients with DM. However, the pharmacological mechanism is not clear. To investigate the mechanisms of SGLT2 inhibitors on HF and DM, we performed target prediction and network analysis by network pharmacology method.Material/MethodsWe selected targets of SGLT2 inhibitors according to SwissTargetPrediction and DrugBank databases and collected therapeutic targets on HF and DM from the Human Gene (GeneCards) and Human Mendelian Inheritance (OMIM) databases. The “Drug-Target” and “Drug-Target-Disease” networks were constructed by using Cytoscape_v3.6.1. Then the protein-protein interaction (PPI) was analyzed by using the String database. Gene Ontology (GO) biological functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed to investigate by using Bioconductor tool for analysis.ResultsThere were 125 effective targets among SGLT2 inhibitors, HF and DM. Through further screening and analyzing, 33 core targets were obtained, such as SRC, MAPK1, NARS, MAPK3 and EGFR. And it is predicted that Rap1 signaling pathway, MAPK signaling pathway, EGFR tyrosine kinase inhibitor resistance, AGE-RAGE signaling pathway in diabetic complications and other signaling pathways were involved in the treatment of HF and DM by SGLT2 inhibitors.ConclusionsOur study elucidated the possible mechanisms of SGLT2 inhibitors from a systemic and holistic perspective based on pharmacological networks. The key targets and pathways will provide new insights for further research on the pharmacological mechanism of SGLT2 inhibitors in the therapy of HF and DM.