CARDIOVASCULAR JOURNAL OF AFRICA • Volume 33, No 6, November/December 2022 304 AFRICA Influence of verapamil on pressure overload-induced ventricular arrhythmias by regulating gene-expression profiles Xianfeng Cheng, Xue Xu, Chengwei Zou, Weidong Jiang Abstract Background: 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 geneexpression identification and functional analysis. Methods: 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. Results: 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. Conclusions: VRP prevented acute pressure overload-induced ventricular arrhythmias, possibly through the hub genes Rac1, Grb2, Rbm8a and Mapk1 as potential targets of VRP. Keywords: verapamil, pressure overload, ventricular arrhythmias, GO analysis, KEGG analysis Submitted 6/3/21, accepted 9/2/22 Published online 16/3/22 Cardiovasc J Afr 2022; 33: 304–312 www.cvja.co.za DOI: 10.5830/CVJA-2022-010 The heart is an exquisitely mechanosensitive organ. The regulation of heart rate is one of its most essential features; however, disorders of the heart’s rhythm can be life threatening. Mechanical changes play critical roles in the regulation of heartbeat in both healthy and unhealthy individuals. Previous studies have shown that acute systolic pressure elevation (afterload) may be associated with the genesis of ventricular arrhythmias (ectopic beats or ventricular tachycardia).1 Previous studies have identified stretch-activated cation non-selective ion channels as key contributors to ventricular arrhythmias in response to mechanical changes.2,3 Ca2+ channels have not been previously found to play an important role in the initial force response to stretch; however, the newly developed model challenges these previous experiments.4 L-type Ca2+ channels belong to a subclass of voltage-gated Ca2+ channels, which are located in the sarcolemma, with the T-tubules facing the sarcoplasmic reticulum junction. The role of the L-type Ca2+ current is to trigger Ca2+ release from the sarcoplasmic reticulum via Ca2+-induced Ca2+ release.5 Recently, Takahashi et al. demonstrated that voltage-gated L-type Ca2+ channels play a critical role in the mechanosensitive Ca2+ response in H9c2 rat cardiomyocytes.4 These studies indicate that an increase in intracellular Ca2+ induced by mechanical stress was primarily triggered by both the activation of stretchactivated ion channels and the L-type Ca2+ channels in neonatal rat cardiomyocytes. This may induce depolarisations that could cause mechanical arrhythmias. The L-type Ca2+ inhibitors nifedipine, diltiazem and verapamil (VRP) reduce the stretch-activated Ca2+ response in a dosedependent manner.4 VRP reduces Ca2+-dependent Ca2+ release and consequently suppresses downstream activities.6 In addition, VRP has recently been reported to be effective in epinephrine and myocardial infarction-induced ventricular arrhythmias7-9 and in delayed afterdepolarisation-related ventricular tachycardia.10 However, VRP suppressed atrioventricular (AV) nodal conduction and could generate AV blocks (AVBs) of various degrees.11 Department of Cardiac Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China Xianfeng Cheng, MD Chengwei Zou, MD, zouchengwei@sdu.edu.cn Department of Cardiac Surgery, Weifang People’s Hospital, Weifang, Shandong, China Xianfeng Cheng, MD Department of Geriatrics, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China Xue Xu, MD Weidong Jiang, MD, jiangholly@aliyun.com Department of Cardiology, Peking University People’s Hospital, Beijing, China Xue Xu, MD
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