ABSTRACT
BACKGROUND: Acute myocardial infarction (AMI) is an age-dependent cardiovascular disease in which cell aging, immunity, and inflammatory factors alter the course; however, cell aging-immune/inflammation signatures in AMI have not been investigated. METHODS: Based on the GEO database to obtain microRNA (miRNA) sequencing, mRNA sequencing and single-cell sequencing data, and utilizing the Seurat package to identify AMI-associated cellular subpopulations. Subsequently, differentially expressed miRNAs and mRNAs were screened to establish a network of competing endogenous RNAs (ceRNAs). Senescence and immunity scores were calculated by single sample gene set enrichment analysis (ssGSEA), ESTIMATE and CIBERSORT algorithms, and the Hmisc package was used to screen for genes with the highest correlation with senescence and immunity scores. Finally, protein-protein interaction (PPI) and molecular docking analyses were performed to predict potential therapeutic agents for the treatment of AMI. RESULTS: Four cell types (Macrophage, Fibroblast, Endothelial cells, CD8 T cells) were identified in AMI, and CD8 T cells exhibited the lowest cell aging activity. A ceRNA network of miRNAs-mNRA interactions was established based on the overlapping genes in differentially expressed miRNAs (DEmiRNAs) target genes and differentially expressed mRNAs (DEmRNAs). Twenty-four marker genes of CD8 T cells were observed. LIMD2 was identified as cell aging-immune/inflammation-related hub gene in AMI. This study also identified a potential therapeutic network of DB03276-LIMD2-AMI, which showed excellent and stable binding status between DB03276-LIMD2. CONCLUSION: This study identified LIMD2 as a cell aging-immune/inflammation-related hub gene. The understanding of the pathogenesis and therapeutic mechanisms of AMI was enriched by the ceRNA network and DB03276-LIMD2-LAMI therapeutic network.
ABSTRACT
Background: Dilated cardiomyopathy (DCM) is a severe manifestation or intermediate stage of cardiovascular disease progression with a significantly poor prognosis. Based on a protein interaction network and molecular docking, the present study determined the genes and mechanism of action of angiotensin-converting enzyme inhibitors (ACEIs) in the treatment of DCM, providing a direction for future studies on ACEI drugs for DCM. Methods: This is a retrospective study. DCM samples and healthy controls were downloaded from the GSE42955 dataset, and the targets of the potential active ingredients were obtained from PubChem. Hub genes in ACEIs were analyzed by constructing network models and a protein-protein interaction (PPI) network using the STRING database and Cytoscape software. Molecular docking was performed using Autodock vina software. Results: Twelve DCM samples and five control samples were finally included. A total of 62 intersected genes were obtained by intersecting the differentially expressed genes with six ACEI target genes. PPI analysis identified 15 intersecting hub genes from these 62 genes. Enrichment analysis showed that the hub genes were associated with T helper type 17 (Th17) cell differentiation as well as the nuclear factor kappa-B (NF-kappa B), interleukin 17 (IL-17), mitogen-activated protein kinase (MAPK), tumor necrosis factor (TNF), phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) (PI3K-Akt), and Toll-like receptor signaling pathways. Molecular docking indicated that the compound Benazepril to produce favorable interactions with TNF proteins with a relatively higher score (-8.3). Conclusions: This study primarily revealed that the preventive and curative effects of ACEI treatment on DCM could be realized through multiple targets and pathways, and its mechanism of action is related to genes such as TNF, vascular endothelial growth factor A (VEGFA), interleukin 6 (IL6), C-C motif chemokine ligand 2 (CCL2), Cyclin D1 (CCND1), and AKT serine/threonine kinase 1 (AKT1), with immune- and inflammation-related signaling pathways involvement.
