Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.
Centre for Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK.
Physiol Genomics. 2024 Feb 1;56(2):167-178. doi: 10.6084/m9.figshare.24449590. Epub 2023 Dec 4.
Heart failure is a major clinical problem, with treatments involving medication, devices, and emerging neuromodulation therapies such as vagus nerve stimulation (VNS). Considering the ongoing interest in using VNS to treat cardiovascular disease it is important to understand the genetic and molecular changes developing in the heart in response to this form of autonomic neuromodulation. This experimental animal (rat) study investigated the immediate transcriptional response of the ventricular myocardium to selective stimulation of vagal efferent activity using an optogenetic approach. Vagal preganglionic neurons in the dorsal motor nucleus of the vagus nerve were genetically targeted to express light-sensitive chimeric channelrhodopsin variant ChIEF, and stimulated using light. RNA sequencing of left ventricular myocardium identified 294 differentially expressed genes (DEGs, false discovery rate <0.05). Qiagen Ingenuity Pathway Analysis (IPA) highlighted 118 canonical pathways that were significantly modulated by vagal activity, of which 14 had a z-score of ≥2/≤-2, including EIF-2, IL-2, Integrin, and NFAT-regulated cardiac hypertrophy. IPA revealed the effect of efferent vagus stimulation on protein synthesis, autophagy, fibrosis, autonomic signalling, inflammation, and hypertrophy. IPA further predicted that the identified DEGs were the targets of 50 upstream regulators, including transcription factors (e.g., MYC, NRF1) and microRNAs (e.g., miR-335-3p, miR-338-3p). These data demonstrate that the vagus nerve has a major impact on myocardial expression of genes involved in regulation of key biological pathways. The transcriptional response of the ventricular myocardium induced by stimulation of vagal efferents is consistent with the beneficial effect of maintained/increased vagal activity on the heart.
心力衰竭是一个主要的临床问题，其治疗方法包括药物治疗、器械治疗和新兴的神经调节治疗，如迷走神经刺激（VNS）。考虑到人们对使用 VNS 治疗心血管疾病的持续兴趣，了解心脏对这种自主神经调节形式的基因和分子变化是很重要的。这项实验动物（大鼠）研究使用光遗传学方法研究了心室心肌对迷走传出活动选择性刺激的即时转录反应。通过基因靶向技术，使迷走神经背核中的节前神经元表达光敏感嵌合通道蛋白 ChIEF，并通过光照刺激。左心室心肌的 RNA 测序确定了 294 个差异表达基因（DEGs，错误发现率 <0.05）。Qiagen Ingenuity Pathway Analysis（IPA）强调了 118 个显著受迷走神经活动调节的经典途径，其中 14 个途径的 z 分数≥2/≤-2，包括 EIF-2、IL-2、整合素和 NFAT 调节的心肌肥大。IPA 显示了传出迷走神经刺激对蛋白质合成、自噬、纤维化、自主信号、炎症和肥大的影响。IPA 进一步预测，鉴定出的 DEGs 是 50 个上游调节剂的靶点，包括转录因子（如 MYC、NRF1）和 microRNAs（如 miR-335-3p、miR-338-3p）。这些数据表明，迷走神经对参与调节关键生物学途径的心肌基因表达有重大影响。刺激迷走传出神经引起的心室心肌转录反应与维持/增加迷走神经活动对心脏的有益影响一致。
