dc.contributor.author | Kellett, DO | |
dc.contributor.author | Aziz, Q | |
dc.contributor.author | Humphries, JD | |
dc.contributor.author | Korsak, A | |
dc.contributor.author | Braga, A | |
dc.contributor.author | Del Arroyo, AG | |
dc.contributor.author | Crescente, M | |
dc.contributor.author | Tinker, A | |
dc.contributor.author | Ackland, GL | |
dc.contributor.author | Gourine, AV | |
dc.date.accessioned | 2024-08-01T10:31:37Z | |
dc.date.available | 2024-08-01T10:31:37Z | |
dc.date.issued | 2024-01-12 | |
dc.identifier.citation | TY - JOUR T1 - Transcriptional response of the heart to vagus nerve stimulation AU - Kellett, Daniel O. AU - Aziz, Qadeer AU - Humphries, Jonathan D. AU - Korsak, Alla AU - Braga, Alice AU - Gutierrez Del Arroyo, Ana AU - Crescente, Marilena AU - Tinker, Andrew AU - Ackland, Gareth L. AU - Gourine, Alexander V. Y1 - 2023/12/04 PY - 2023 DA - 2024/02/01 N1 - doi: 10.1152/physiolgenomics.00095.2023 DO - 10.1152/physiolgenomics.00095.2023 T2 - Physiological Genomics JF - Physiological Genomics SP - 167 EP - 178 VL - 56 IS - 2 PB - American Physiological Society N2 - 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 the left ventricular myocardium identified 294 differentially expressed genes (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 signaling, inflammation, and hypertrophy. IPA further predicted that the identified differentially expressed genes were the targets of 50 upstream regulators, including transcription factors (e.g., MYC and NRF1) and microRNAs (e.g., miR-335-3p and miR-338-3p). These data demonstrate that the vagus nerve has a major impact on the myocardial expression of genes involved in the 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.NEW & NOTEWORTHY This experimental animal study investigated the immediate transcriptional response of the ventricular myocardium to selective stimulation of vagal efferent activity. Vagal stimulation induced significant transcriptional changes in the heart involving the pathways controlling autonomic signaling, inflammation, fibrosis, and hypertrophy. This study provides the first direct evidence that myocardial gene expression is modulated by the activity of the autonomic nervous system. AB - 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 the left ventricular myocardium identified 294 differentially expressed genes (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 signaling, inflammation, and hypertrophy. IPA further predicted that the identified differentially expressed genes were the targets of 50 upstream regulators, including transcription factors (e.g., MYC and NRF1) and microRNAs (e.g., miR-335-3p and miR-338-3p). These data demonstrate that the vagus nerve has a major impact on the myocardial expression of genes involved in the 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.NEW & NOTEWORTHY This experimental animal study investigated the immediate transcriptional response of the ventricular myocardium to selective stimulation of vagal efferent activity. Vagal stimulation induced significant transcriptional changes in the heart involving the pathways controlling autonomic signaling, inflammation, fibrosis, and hypertrophy. This study provides the first direct evidence that myocardial gene expression is modulated by the activity of the autonomic nervous system. SN - 1094-8341 M3 - doi: 10.1152/physiolgenomics.00095.2023 UR - https://doi.org/10.1152/physiolgenomics.00095.2023 Y2 - 2024/08/01 ER - | en_US |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/98548 | |
dc.description.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. | en_US |
dc.format.extent | 167 - 178 | |
dc.language | eng | |
dc.publisher | American Physiological Society | en_US |
dc.relation.ispartof | Physiol Genomics | |
dc.rights | Licensed under Creative Commons Attribution CC-BY 4.0. Published by the American Physiological Society. | |
dc.subject | RNA sequencing | en_US |
dc.subject | autonomic nervous system | en_US |
dc.subject | heart | en_US |
dc.subject | transcriptome | en_US |
dc.subject | vagus nerve. | en_US |
dc.subject | Animals | en_US |
dc.subject | Vagus Nerve Stimulation | en_US |
dc.subject | Rats | en_US |
dc.subject | Vagus Nerve | en_US |
dc.subject | Heart | en_US |
dc.subject | Male | en_US |
dc.subject | Myocardium | en_US |
dc.subject | Rats, Sprague-Dawley | en_US |
dc.subject | Optogenetics | en_US |
dc.subject | Gene Expression Regulation | en_US |
dc.subject | Transcription, Genetic | en_US |
dc.subject | Gene Expression Profiling | en_US |
dc.title | Transcriptional response of the heart to vagus nerve stimulation. | en_US |
dc.type | Article | en_US |
dc.rights.holder | © 2024 The Authors. | |
dc.identifier.doi | 10.6084/m9.figshare.24449590 | |
dc.identifier.doi | doi.org/10.1152/physiolgenomics.00095.2023 | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/39071113 | en_US |
pubs.issue | 2 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 56 | en_US |
rioxxterms.funder | Default funder | en_US |
rioxxterms.identifier.project | Default project | en_US |
qmul.funder | Cardiac vagus and exercise in health and disease::British Heart Foundation | en_US |
rioxxterms.funder.project | b215eee3-195d-4c4f-a85d-169a4331c138 | en_US |