Systematic investigation of the underlying mechanisms of GLP-1 receptor agonists to prevent myocardial infarction in patients with type 2 diabetes mellitus using network pharmacology

Abstract

Background: Several clinical trials have demonstrated that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) reduce the incidence of non-fatal myocardial infarction (MI) in patients with type 2 diabetes mellitus (T2DM). However, the underlying mechanism remains unclear. In this study, we applied a network pharmacology method to investigate the mechanisms by which GLP-1RAs reduce MI occurrence in patients with T2DM.Methods: Targets of three GLP-1RAs (liraglutide, semaglutide, and albiglutide), T2DM, and MI were retrieved from online databases. The intersection process and associated targets retrieval were employed to obtain the related targets of GLP-1RAs against T2DM and MI. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genes (KEGG) enrichment analyses were performed. The STRING database was used to obtain the protein-protein interaction (PPI) network, and Cytoscape was used to identify core targets, transcription factors, and modules.Results: A total of 198 targets were retrieved for the three drugs and 511 targets for T2DM with MI. Finally, 51 related targets, including 31 intersection targets and 20 associated targets, were predicted to interfere with the progression of T2DM and MI on using GLP-1RAs. The STRING database was used to establish a PPI network comprising 46 nodes and 175 edges. The PPI network was analyzed using Cytoscape, and seven core targets were screened: AGT, TGFB1, STAT3, TIMP1, MMP9, MMP1, and MMP2. The transcription factor MAFB regulates all seven core targets. The cluster analysis generated three modules. The GO analysis for 51 targets indicated that the terms were mainly enriched in the extracellular matrix, angiotensin, platelets, and endopeptidase. The results of KEGG analysis revealed that the 51 targets primarily participated in the renin-angiotensin system, complement and coagulation cascades, hypertrophic cardiomyopathy, and AGE-RAGE signaling pathway in diabetic complications.Conclusion: GLP-1RAs exert multi-dimensional effects on reducing the occurrence of MI in T2DM patients by interfering with targets, biological processes, and cellular signaling pathways related to atheromatous plaque, myocardial remodeling, and thrombosis.

Cardiomyocyte-specific overexpression of GPR22 ameliorates cardiac injury in mice with acute myocardial infarction

“…Beyond its impact on cardiac function, neuropsychiatric disorders following circulatory disorders are significantly more common and result in higher mortality rates post-MI compared to individuals without MI [ 31 ]. The development of novel diagnostic techniques and therapeutic strategies through preclinical studies and clinical validation has been a crucial focus in cardiovascular research [ 32 – 34 ].…”

“…Despite the widespread use of G protein-coupled receptor (GPCR)-targeted drugs in cardiovascular diseases, such as those targeting β-Adrenergic receptors (βARs), angiotensin II type 1 receptors (AT1Rs), and glucagon-like peptide-1 (GLP-1) receptors [32,45], only specific types of GPCRs, including β2-adrenergic receptors, opioid receptors, and adenosine receptors, have been identified to exert cardiomyocyte protective functions against ischemic stress [21,46,47]. In our previous study, we have demonstrated a cardiomyocyte-specific expression of GPR22 in the myocardium [18].…”

Ultrasound-targeted semaglutide-loaded PEG-nanoliposomes microbubble destruction protects diabetic cardiomyopathy by activating PI3K/Akt/Nrf2 signaling pathway

“…Several clinical studies have shown that semaglutide can effectively increase the survival rate of patients after myocardial infarction and improve the cardiac function of diabetic patients [ 13 ]. Therefore, Semaglutide was used as a model drug in this study [ 25 ]. At the same time, in order to overcome the defects of poor stability, easy degradation and low bioavailability of biomacromolecule drugs in vivo , we applied a new water-in-water emulsification technology combined with secondary freeze-drying method, and used PEGylated phospholipids as membrane material to prepare a new type of PEGylated long circulating liposomes.…”

Updates on New Therapies for Patients with CKD

“…However preclinical or clinical studies remain to be performed to confirm these effects. 82 In Supplementary Table S3 , we summarize landmark RCTs evaluating effects of oral and injectable GLP1 receptor agonists in reducing CV events. 50 , 51 , 52 , 53 , 83 A recent meta-analysis of recently published RCTs reported reduction in CV events by 14% (HR 0.86, 95% CI: 0.80–0.93), in all-cause mortality by 12% (HR 0.88, 95% CI: 0.82–0.94 and in composite renal outcome by 21% (HR 0.79, 95% CI: 0.73–0.87).…”