GLP1R attenuates sympathetic response to high glucose via carotid body inhibition

Audrys G. Pauza, Pratik Thakka, Tatjana Tasic, Igor Felippe, Paul Bishop, Michael P. Greenwood, Kristina Rysevaite-Kyguoliene, Julia Ast, Johannes Broichhagen, David Hodson, Helio C Salgado, Dainius H. Pauza, Nina Japundzic-Zigon, Julian F.R. Paton, David Murphy

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Abstract

Background: Aberrant sympathetic nerve activity exacerbates cardiovascular risk in hypertension and diabetes, which are common comorbidities, yet clinically sympathetic nerve activity remains poorly controlled. The hypertensive diabetic state is associated with increased reflex sensitivity and tonic drive from the peripheral chemoreceptors, the cause of which is unknown. We have previously shown hypertension to be critically dependent on the carotid body (CB) input in spontaneously hypertensive rat, a model that also exhibits a number of diabetic traits. CB overstimulation by insulin and leptin has been similarly implicated in the development of increased sympathetic nerve activity in metabolic syndrome and obesity. Thus, we hypothesized that in hypertensive diabetic state (spontaneously hypertensive rat), the CB is sensitized by altered metabolic signaling causing excessive sympathetic activity levels and dysfunctional reflex regulation.

Methods: Using a hypothesis-free RNA-seq approach, we investigated potential molecular targets implicated in energy metabolism mediating CB sensitization and its regulation of sympathetic outflow in experimental hypertension. Identified targets were characterized using molecular and functional techniques assessing peripheral chemoreflex sensitivity in situ and in vivo.

Results: We discovered GLP1R (glucagon-like peptide-1 receptor) expression in the CBs of rat and human and showed that its decreased expression is linked to sympathetic hyperactivity in rats with cardiometabolic disease. We demonstrate GLP1R to be localized to CB chemosensory cells, while targeted administration of GLP1R agonist to the CB lowered its basal discharge and attenuated chemoreflex-evoked blood pressure and sympathetic responses. Importantly, hyperglycemia-induced peripheral chemoreflex sensitization and associated basal sympathetic overactivity were abolished by GLP1R activation in the CB suggesting a role in a homeostatic response to high blood glucose.

Conclusions: We show GLP1 (glucagon-like peptide-1) to modulate the peripheral chemoreflex acting on the CB, supporting this organ as a multimodal receptor. Our findings pinpoint CBs as potential targets for ameliorating excessive sympathetic activity using GLP1R agonists in the hypertensive-diabetic condition.
Original languageEnglish
Pages (from-to)694-707
Number of pages14
JournalCirculation
Volume130
Issue number5
Early online date1 Feb 2022
DOIs
Publication statusPublished - 4 Mar 2022

Keywords

  • hypertension
  • obesity
  • risk factors
  • carotid body
  • insulin

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology

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