Influence of verapamil on pressure overload-induced ventricular arrhythmias by regulating gene-expression profiles.

Abstract

Life-threatening ventricular arrhythmias can lead to sudden cardiac death in patients. This study aimed to investigate the changes in gene profiles involved when verapamil (VRP) affects increased wall stress (pressure overload)-induced ventricular arrhythmias, thus revealing the potential causative molecular mechanisms and therapeutic targets through gene-expression identification and functional analysis. Animal models with wall stress-induced ventricular arrhythmias were established. Low (0.5 mg/kg) and high (1 mg/kg) doses of VRP were administered intravenously 10 minutes before transverse aortic constriction, and average ventricular arrhythmia scores were calculated. Next, we evaluated the molecular role of VRP by characterising differential gene-expression profiles between VRP-pretreated (1 mg/kg) and control groups using RNA-sequencing technology. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to reveal molecular function. A protein-protein interaction (PPI) network was then developed. VRP exerted its anti-arrhythmic effects in response to increases in left ventricular (LV) afterload. We detected differentially expressed genes (DEGs), of which 36 were upregulated and 1 397 downregulated, between the VRP-pretreated and model groups during acute increases in LV wall stress. GO analysis demonstrated that the DEGs were associated with cytoskeletal protein binding. KEGG analysis showed that enriched pathways were mainly distributed in adherens junctions, actin cytoskeleton regulation and the MAPK signalling pathway. Centralities analysis of the PPI identified Rac1, Grb2, Rbm8a and Mapk1 as hub genes. VRP prevented acute pressure overload-induced ventricular arrhythmias, possibly through the hub genes Rac1, Grb2, Rbm8a and Mapk1 as potential targets of VRP.