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

Abstract

Purpose Diabetes mellitus (DM) is a major risk factor for the development of heart failure (HF). Sodium-glucose co-transporter 2 (SGLT2) inhibitors have 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 in DM with HF, we performed target prediction and network analysis by a network pharmacology method. Methods We selected targets of SGLT2 inhibitors and DM status with HF from databases and studies. The “Drug-Target” and “Drug-Target-Disease” networks were constructed using Cytoscape. Then the protein–protein interaction (PPI) was analyzed using the STRING database. Gene Ontology (GO) biological functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were performed to investigate using the Bioconductor tool for analysis. Results There were 125 effective targets between SGLT2 inhibitors and DM status with HF. Through further screening, 33 core targets were obtained, including SRC, MAPK1, NARS, MAPK3 and EGFR. It was predicted that the 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 DM with HF by SGLT2 inhibitors. Conclusion Our 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 treatment of DM with HF.

Dapagliflozin alleviates myocardial ischemia/reperfusion injury by reducing ferroptosis via MAPK signaling inhibition

“…The biological process and module functions were mainly involved in the regulation of the MAPK cascade and MAP or MAPK kinase activity. Pathways were enriched in the AGE-RAGE signaling pathway in diabetic complications, the TNF signaling pathway, the Rap1 signaling pathway and the MAPK signaling pathway, which was consistent with previous studies in T2DM patients with heart failure ( Yue et al, 2021 ; Mai et al, 2022 ). Furthermore, after crossing with the ferroptosis database, a PPI network with the best score identified the core targets, including MAPK1 and MAPK14, which are involved in the MAPK pathway.…”

Characterization of the SGLT2 Interaction Network and Its Regulation by SGLT2 Inhibitors: A Bioinformatic Analysis

“…In a recent study, Mai et al investigated the pharmacological mechanisms of SGLT2i network pharmacology focused on genes associated with DM and HF. They utilized the Swiss Target Prediction tool for the target prediction of selected SGLT2i (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) ( Mai et al, 2022 ). They identified 33 core SGLT2i targets including SRC, MAPK1, NARS, MAPK3, and EGFR.…”

Identification of Potentially Functional Circular RNA/Long Noncoding RNA-MicroRNA-mRNA Regulatory Networks Associated with Vascular Injury in Type 2 Diabetes Mellitus by Integrated Microarray Analysis

“…A prior research elucidated that dynamic change of serum Alb level was correlated with T2DM risk [33]. Also, it was noted in another research that MAPK3 and MAPK1 were involved in heart failure caused by diabetes [34]. Hras has been demonstrated to accelerate glucose-induced apoptosis of retinal capillary cells in diabetes [35].…”