Author: Daniel O Kellett1, Qadeer Aziz1,2, Jonathan D Humphries3, Alla Korsak1, Alice Braga1, Ana Gutierrez Del Arroyo2, Marilena Crescente3, Andrew Tinker2, Gareth L Ackland4, Alexander V Gourine1
Affiliation: <sup>1</sup> Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.
<sup>2</sup> Centre for Clinical Pharmacology and Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK.
<sup>3</sup> Department of Life Sciences, Manchester Metropolitan University, Manchester, UK.
<sup>4</sup> Translational Medicine and Therapeutics, William Harvey Research Institute, Queen Mary University of London, London, UK.
Conference/Journal: Physiol Genomics
Date published: 2024 Feb 1
Other:
Volume ID: 56 , Issue ID: 2 , Pages: 167-178 , Special Notes: doi: 10.6084/m9.figshare.24449590. , Word Count: 265
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.
Keywords: RNA sequencing; autonomic nervous system; heart; transcriptome; vagus nerve..
PMID: 39071113 PMCID: PMC7616044 DOI: 10.6084/m9.figshare.24449590