Study on the pharmacological mechanisms of sodium-glucose co-transporter 2 inhibitors in obesity-related atrial fibrillation based on network pharmacology and experimental verification

Qianqian Zhao; Peng Wang; Maoxiang Zhao; Jing Hong; Nan Zhang; Kun Lin; Yang Li

doi:10.21037/atm-23-1321

Study on the pharmacological mechanisms of sodium-glucose co-transporter 2 inhibitors in obesity-related atrial fibrillation based on network pharmacology and experimental verification

Ann Transl Med. 2023 Apr 28;11(8):300. doi: 10.21037/atm-23-1321. Epub 2023 Apr 30.

Authors

Qianqian Zhao^#^{1

2}, Peng Wang^#^{1

3}, Maoxiang Zhao², Jing Hong⁴, Nan Zhang¹, Kun Lin⁵, Yang Li²

Affiliations

¹ Postgraduate School, Medical School of Chinese People's Liberation Army (PLA), Beijing, China.
² Department of Cardiology, The Sixth Medical Center, Chinese PLA General Hospital, Beijing, China.
³ Department of Traditional Chinese Medicine, Chinese PLA General Hospital, Beijing, China.
⁴ Department of Traditional Chinese Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
⁵ Department of Outpatient, The First Medical Center, Chinese PLA General Hospital, Beijing, China.

^# Contributed equally.

Abstract

Background: Obesity is an independently risk factor of atrial fibrillation (AF). It is likely that the global burden of AF will escalate due to the current obesity epidemic. Weight loss can effectively reduce the risk of AF, while sodium-glucose co-transporter 2 inhibitors (SGLT2i) can reduce body weight, so SGLT2i are potentially effective for obesity-related AF. SGLT2i are a novel type of oral medication. This current study used network pharmacology to examine the potential mechanisms of SGLT2i in the treatment of obesity-related AF, and the therapeutic effects were assessed in vivo.

Methods: Potential gene targets for SGLT2i in treating obesity-related AF were identified from public database. Cytoscape V3.7.1 was used to construct the "Drug-Target" and "Drug-Target-Disease" networks. The STRING database was applied to investigate the protein-protein interactions (PPIs). Additionally, the Bioconductor tools were used to analyze the Gene Ontology (GO) biological functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. The efficacy of SGLT2i in treating obesity-related AF was investigated in vivo using a diet-induced obese C57BL/6J male mouse model. A number of indicators were assessed, including invasive electrophysiology, testing of blood samples, and expression detection of pathway targets. These experiments were used to verify the targets mined by network pharmacology.

Results: The results indicated that SGLT2i had 80 potential target genes during the treatment of obesity-related AF, and 10 hub genes were obtained by further screening. It was predicted that the treatment of obesity-related AF by SGLT2i involved the advanced glycation end product (AGE)-receptor for advanced glycation end product (RAGE) signaling pathway and other signaling pathways. In in vivo experiments, administration of SGLT2i (the SGLT2i + DIO group) resulted in a lower AF induction rate (P<0.05), decreased serum AGEs/soluble RAGE (sRAGE) ratio (P<0.01), and decreased expression of NADPH oxidase 2 (NOX2) (P<0.05) compared to untreated DIO mice (the DIO group).

Conclusions: In this study, pharmacological network analysis and in vivo experiments demonstrated that SGLT2i acts on obesity-related AF by inhibiting the AGE-RAGE signaling pathway. These results offer fresh perspectives on the pharmacological actions of SGLT2i in treating obesity-related AF.

Keywords: AGE-RAGE signaling pathway; Atrial fibrillation (AF); NADPH oxidase 2; obesity; sodium-glucose co-transporter 2 inhibitors.