Exploration of Mechanisms of Sacubitril/Valsartan in the Treatment of Cardiac Arrhythmias Using a Network Pharmacology Approach

Figures

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  FIGURE 1. A schematic diagram showing the network pharmacological method for identifying targets, PPI network, biological processes, and key pathways of SV acting on cardiac arrhythmia (CA). All known targets of Sacubitril/valsartan (SV) and CA were obtained through online databases. Anti-arrhythmia targets of SV were identified. After constructing a protein-protein interaction (PPI) network and determining the potential targets of SV concerning CA, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were carried out. Finally, the SV-GO-KEGG-CA network was generated. CTD: comparative toxicology genomics database.

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  FIGURE 2. PPI network of the DPTs of SV constructed by STRING.

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  FIGURE 3. The PPI network for the DPTs and indirect protein targets (IPTs) of SV was constructed using STRING and no more than 50 interactors on the first and second shell were set as the cut-off criteria with the highest confidence (score = 0.9). The IPTs and DPTs were visualized by Cytoscape (v.3.8.2). The red to yellow rectangles represent scores from high to low.

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  FIGURE 4. Acquisition of core target proteins and protein-protein interaction network. (A) SV-related drug target proteins [DTPs and indirect target proteins (ITPs)] were obtained from Drugbank Data and STRING. The top 400 CA-related genes were selected from GeneCards and CTD. The intersection of drug target protein genes (DTPs and ITPs) and the top two CA-related genes were selected by the Venn diagram. There were seven core target proteins (Red Pentagram). (B) A PPI network of the antiarrhythmic targets of SV was generated by the STRING database with medium confidence (0.400).

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  FIGURE 5. GO enrichment analysis of seven target genes (ACE, CAV1, AGT, REN, ADRB2, TP53, and ALB) for anti-arrhythmias with SV. (A) Biological process, cellular component and molecular function of Go enrichment of the target genes. (B,C) The bubble diagram shows the top 20 enriched molecular function and biological process respectively.

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  FIGURE 6. Pathway enrichment analyses of seven target genes (ACE, CAV1, AGT, REN, ADRB2, TP53, and ALB) for the treatment of CA with SV. (A) The bubble chart shows the top 20 enriched KEGG pathways. The x-axis indicates the Enrichment Factor and the intensity of different colors indicates the adjusted p-value. (B) The histogram shows the top 20 enriched KEGG pathways. The x-axis represents the enriched Gene Percentage (%) and the intensity of different colors indicates the adjusted p-value.

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  FIGURE 7. The integrated SV-GO-KEGG-Anti-arrhythmia network was visualized by Cytoscape.