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Transcriptional response of the heart to vagus nerve stimulation

Kellett, Daniel O; Aziz, Qadeer; Humphries, Jonathan D; Korsak, Alla; Braga, Alice; Gutierrez Del Arroyo, Ana; Crescente, Marilena; ... Gourine, Alexander V; + view all (2023) Transcriptional response of the heart to vagus nerve stimulation. Physiological Genomics 10.1152/physiolgenomics.00095.2023. (In press).

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Abstract

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.

Type: Article
Title: Transcriptional response of the heart to vagus nerve stimulation
Location: United States
DOI: 10.1152/physiolgenomics.00095.2023
Publisher version: https://doi.org/10.1152/physiolgenomics.00095.2023
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: autonomic nervous system, heart, RNA sequencing, transcriptome, vagus nerve
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10184882
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