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Systemic administration of choline acetyltransferase decreases blood pressure in murine hypertension
Acetylcholine (ACh) decreases blood pressure by stimulating endothelium nitric oxide-dependent vasodilation in resistance arterioles. Normal plasma contains choline acetyltransferase (ChAT) and its biosynthetic product ACh at appreciable concentrations to potentially act upon the endothelium to affe...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8529785/ https://www.ncbi.nlm.nih.gov/pubmed/34674633 http://dx.doi.org/10.1186/s10020-021-00380-6 |
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author | Stiegler, Andrew Li, Jian-Hua Shah, Vivek Tsaava, Tea Tynan, Aisling Yang, Huan Tamari, Yehuda Brines, Michael Tracey, Kevin J. Chavan, Sangeeta S. |
author_facet | Stiegler, Andrew Li, Jian-Hua Shah, Vivek Tsaava, Tea Tynan, Aisling Yang, Huan Tamari, Yehuda Brines, Michael Tracey, Kevin J. Chavan, Sangeeta S. |
author_sort | Stiegler, Andrew |
collection | PubMed |
description | Acetylcholine (ACh) decreases blood pressure by stimulating endothelium nitric oxide-dependent vasodilation in resistance arterioles. Normal plasma contains choline acetyltransferase (ChAT) and its biosynthetic product ACh at appreciable concentrations to potentially act upon the endothelium to affect blood pressure. Recently we discovered a T-cell subset expressing ChAT (T(ChAT)), whereby genetic ablation of ChAT in these cells produces hypertension, indicating that production of ACh by T(ChAT) regulates blood pressure. Accordingly, we reasoned that increasing systemic ChAT concentrations might induce vasodilation and reduce blood pressure. To evaluate this possibility, recombinant ChAT was administered intraperitoneally to mice having angiotensin II-induced hypertension. This intervention significantly and dose-dependently decreased mean arterial pressure. ChAT-mediated attenuation of blood pressure was reversed by administration of the nitric oxide synthesis blocker l-nitro arginine methyl ester, indicating ChAT administration decreases blood pressure by stimulating nitic oxide dependent vasodilation, consistent with an effect of ACh on the endothelium. To prolong the half life of circulating ChAT, the molecule was modified by covalently attaching repeating units of polyethylene glycol (PEG), resulting in enzymatically active PEG-ChAT. Administration of PEG-ChAT to hypertensive mice decreased mean arterial pressure with a longer response duration when compared to ChAT. Together these findings suggest further studies are warranted on the role of ChAT in hypertension. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-021-00380-6. |
format | Online Article Text |
id | pubmed-8529785 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-85297852021-10-22 Systemic administration of choline acetyltransferase decreases blood pressure in murine hypertension Stiegler, Andrew Li, Jian-Hua Shah, Vivek Tsaava, Tea Tynan, Aisling Yang, Huan Tamari, Yehuda Brines, Michael Tracey, Kevin J. Chavan, Sangeeta S. Mol Med Research Article Acetylcholine (ACh) decreases blood pressure by stimulating endothelium nitric oxide-dependent vasodilation in resistance arterioles. Normal plasma contains choline acetyltransferase (ChAT) and its biosynthetic product ACh at appreciable concentrations to potentially act upon the endothelium to affect blood pressure. Recently we discovered a T-cell subset expressing ChAT (T(ChAT)), whereby genetic ablation of ChAT in these cells produces hypertension, indicating that production of ACh by T(ChAT) regulates blood pressure. Accordingly, we reasoned that increasing systemic ChAT concentrations might induce vasodilation and reduce blood pressure. To evaluate this possibility, recombinant ChAT was administered intraperitoneally to mice having angiotensin II-induced hypertension. This intervention significantly and dose-dependently decreased mean arterial pressure. ChAT-mediated attenuation of blood pressure was reversed by administration of the nitric oxide synthesis blocker l-nitro arginine methyl ester, indicating ChAT administration decreases blood pressure by stimulating nitic oxide dependent vasodilation, consistent with an effect of ACh on the endothelium. To prolong the half life of circulating ChAT, the molecule was modified by covalently attaching repeating units of polyethylene glycol (PEG), resulting in enzymatically active PEG-ChAT. Administration of PEG-ChAT to hypertensive mice decreased mean arterial pressure with a longer response duration when compared to ChAT. Together these findings suggest further studies are warranted on the role of ChAT in hypertension. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-021-00380-6. BioMed Central 2021-10-21 /pmc/articles/PMC8529785/ /pubmed/34674633 http://dx.doi.org/10.1186/s10020-021-00380-6 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Stiegler, Andrew Li, Jian-Hua Shah, Vivek Tsaava, Tea Tynan, Aisling Yang, Huan Tamari, Yehuda Brines, Michael Tracey, Kevin J. Chavan, Sangeeta S. Systemic administration of choline acetyltransferase decreases blood pressure in murine hypertension |
title | Systemic administration of choline acetyltransferase decreases blood pressure in murine hypertension |
title_full | Systemic administration of choline acetyltransferase decreases blood pressure in murine hypertension |
title_fullStr | Systemic administration of choline acetyltransferase decreases blood pressure in murine hypertension |
title_full_unstemmed | Systemic administration of choline acetyltransferase decreases blood pressure in murine hypertension |
title_short | Systemic administration of choline acetyltransferase decreases blood pressure in murine hypertension |
title_sort | systemic administration of choline acetyltransferase decreases blood pressure in murine hypertension |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8529785/ https://www.ncbi.nlm.nih.gov/pubmed/34674633 http://dx.doi.org/10.1186/s10020-021-00380-6 |
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