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Downregulation of Orexin Receptor in Hypothalamic Paraventricular Nucleus Decreases Blood Pressure in Obese Zucker Rats

BACKGROUND: Orexin and its receptors are critical regulating sympathetic vasomotor tone under physiological and pathophysiological conditions. Orexin receptor 1 (OXR1) is upregulated in the paraventricular nucleus (PVN) in the hypothalamus and contributes to increased sympathetic outflow in obese Zu...

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Autores principales: Zhou, Jing‐Jing, Ma, Hui‐Jie, Shao, Jianying, Wei, Yan, Zhang, Xiangjian, Zhang, Yi, Li, De‐Pei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662376/
https://www.ncbi.nlm.nih.gov/pubmed/31213116
http://dx.doi.org/10.1161/JAHA.118.011434
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author Zhou, Jing‐Jing
Ma, Hui‐Jie
Shao, Jianying
Wei, Yan
Zhang, Xiangjian
Zhang, Yi
Li, De‐Pei
author_facet Zhou, Jing‐Jing
Ma, Hui‐Jie
Shao, Jianying
Wei, Yan
Zhang, Xiangjian
Zhang, Yi
Li, De‐Pei
author_sort Zhou, Jing‐Jing
collection PubMed
description BACKGROUND: Orexin and its receptors are critical regulating sympathetic vasomotor tone under physiological and pathophysiological conditions. Orexin receptor 1 (OXR1) is upregulated in the paraventricular nucleus (PVN) in the hypothalamus and contributes to increased sympathetic outflow in obese Zucker rats (OZRs). We hypothesized that silencing OXR1 expression in the PVN decreases heightened blood pressure and elevated sympathetic outflow in OZRs. METHODS AND RESULTS: An adeno‐associated virus (AAV) vector containing a short hairpin RNA (shRNA) targeting rat OXR1 was designed to silence OXR1 expression in the PVN. The AAV‐OXR1‐shRNA or scrambled shRNA was injected into the PVN in OZRs. The arterial blood pressure in free‐moving OZRs was continuously monitored by using a telemetry approach. The firing activity of spinally projecting PVN neurons in rat brain slices was recorded 3 to 4 weeks after injection of viral vectors. The free‐moving OZRs treated with AAV‐OXR1‐shRNA had markedly lower OXR1 expression and lower mean arterial blood pressure, heart rate, and ratio of low‐ to high‐frequency components of heart rate variability compared with OZRs treated with scrambled shRNA. Furthermore, AAV‐OXR1‐shRNA treatment markedly reduced renal sympathetic nerve activity and attenuated sympathoexcitatory response induced by microinjection of orexin A into the PVN. In addition, treatment with AAV‐OXR1‐shRNA substantially decreased the basal firing activity of spinally projecting PVN neurons in OZRs and attenuated the excitatory effect of orexin A on the firing activity of these neurons. CONCLUSIONS: These data suggest that chronic downregulation of OXR1 expression in the PVN reduces sympathetic vasomotor tone in obesity‐related hypertension.
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spelling pubmed-66623762019-08-02 Downregulation of Orexin Receptor in Hypothalamic Paraventricular Nucleus Decreases Blood Pressure in Obese Zucker Rats Zhou, Jing‐Jing Ma, Hui‐Jie Shao, Jianying Wei, Yan Zhang, Xiangjian Zhang, Yi Li, De‐Pei J Am Heart Assoc Original Research BACKGROUND: Orexin and its receptors are critical regulating sympathetic vasomotor tone under physiological and pathophysiological conditions. Orexin receptor 1 (OXR1) is upregulated in the paraventricular nucleus (PVN) in the hypothalamus and contributes to increased sympathetic outflow in obese Zucker rats (OZRs). We hypothesized that silencing OXR1 expression in the PVN decreases heightened blood pressure and elevated sympathetic outflow in OZRs. METHODS AND RESULTS: An adeno‐associated virus (AAV) vector containing a short hairpin RNA (shRNA) targeting rat OXR1 was designed to silence OXR1 expression in the PVN. The AAV‐OXR1‐shRNA or scrambled shRNA was injected into the PVN in OZRs. The arterial blood pressure in free‐moving OZRs was continuously monitored by using a telemetry approach. The firing activity of spinally projecting PVN neurons in rat brain slices was recorded 3 to 4 weeks after injection of viral vectors. The free‐moving OZRs treated with AAV‐OXR1‐shRNA had markedly lower OXR1 expression and lower mean arterial blood pressure, heart rate, and ratio of low‐ to high‐frequency components of heart rate variability compared with OZRs treated with scrambled shRNA. Furthermore, AAV‐OXR1‐shRNA treatment markedly reduced renal sympathetic nerve activity and attenuated sympathoexcitatory response induced by microinjection of orexin A into the PVN. In addition, treatment with AAV‐OXR1‐shRNA substantially decreased the basal firing activity of spinally projecting PVN neurons in OZRs and attenuated the excitatory effect of orexin A on the firing activity of these neurons. CONCLUSIONS: These data suggest that chronic downregulation of OXR1 expression in the PVN reduces sympathetic vasomotor tone in obesity‐related hypertension. John Wiley and Sons Inc. 2019-06-19 /pmc/articles/PMC6662376/ /pubmed/31213116 http://dx.doi.org/10.1161/JAHA.118.011434 Text en © 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Research
Zhou, Jing‐Jing
Ma, Hui‐Jie
Shao, Jianying
Wei, Yan
Zhang, Xiangjian
Zhang, Yi
Li, De‐Pei
Downregulation of Orexin Receptor in Hypothalamic Paraventricular Nucleus Decreases Blood Pressure in Obese Zucker Rats
title Downregulation of Orexin Receptor in Hypothalamic Paraventricular Nucleus Decreases Blood Pressure in Obese Zucker Rats
title_full Downregulation of Orexin Receptor in Hypothalamic Paraventricular Nucleus Decreases Blood Pressure in Obese Zucker Rats
title_fullStr Downregulation of Orexin Receptor in Hypothalamic Paraventricular Nucleus Decreases Blood Pressure in Obese Zucker Rats
title_full_unstemmed Downregulation of Orexin Receptor in Hypothalamic Paraventricular Nucleus Decreases Blood Pressure in Obese Zucker Rats
title_short Downregulation of Orexin Receptor in Hypothalamic Paraventricular Nucleus Decreases Blood Pressure in Obese Zucker Rats
title_sort downregulation of orexin receptor in hypothalamic paraventricular nucleus decreases blood pressure in obese zucker rats
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662376/
https://www.ncbi.nlm.nih.gov/pubmed/31213116
http://dx.doi.org/10.1161/JAHA.118.011434
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