Department of Cardiac Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Cardiac Surgery, Weifang People's Hospital, Weifang, Shandong, China.
Department of Geriatrics, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China; Department of Cardiology, Peking University People's Hospital, Beijing, China.
Cardiovasc J Afr. 2022;33(6):304-312. doi: 10.5830/CVJA-2022-010. Epub 2022 Mar 16.
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 , , and as hub genes.
VRP prevented acute pressure overload-induced ventricular arrhythmias, possibly through the hub genes , , and as potential targets of VRP.
危及生命的室性心律失常可导致患者心源性猝死。本研究旨在探讨维拉帕米（VRP）影响增加壁应（压力超负荷）诱导的室性心律失常时涉及的基因谱变化，从而通过基因表达鉴定和功能分析揭示潜在的致病分子机制和治疗靶点。
建立壁应诱导室性心律失常的动物模型。在横主动脉缩窄前 10 分钟静脉注射低（0.5mg/kg）和高（1mg/kg）剂量的 VRP，并计算平均室性心律失常评分。接下来，我们使用 RNA 测序技术评估 VRP 预处理（1mg/kg）和对照组之间的差异基因表达谱，以确定 VRP 的分子作用。基因本体（GO）和京都基因与基因组百科全书（KEGG）富集分析用于揭示分子功能。然后构建蛋白质-蛋白质相互作用（PPI）网络。
VRP 对左心室（LV）后负荷增加发挥抗心律失常作用。我们在急性 LV 壁应增加期间检测到 VRP 预处理和模型组之间的差异表达基因（DEGs），其中 36 个上调，1397 个下调。GO 分析表明，DEGs 与细胞骨架蛋白结合有关。KEGG 分析表明，富集途径主要分布在黏着连接、肌动蛋白细胞骨架调节和 MAPK 信号通路中。PPI 的中心性分析确定、、和 为枢纽基因。
VRP 可预防急性压力超负荷诱导的室性心律失常，可能通过枢纽基因、、和 作为 VRP 的潜在靶点。
