Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Stiegler, Andrew, Li, Jian-Hua, Shah, Vivek, Tsaava, Tea, Tynan, Aisling, Yang, Huan, Tamari, Yehuda, Brines, Michael, Tracey, Kevin J., Chavan, Sangeeta S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
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
_version_ 1784586539047583744
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
work_keys_str_mv AT stieglerandrew systemicadministrationofcholineacetyltransferasedecreasesbloodpressureinmurinehypertension
AT lijianhua systemicadministrationofcholineacetyltransferasedecreasesbloodpressureinmurinehypertension
AT shahvivek systemicadministrationofcholineacetyltransferasedecreasesbloodpressureinmurinehypertension
AT tsaavatea systemicadministrationofcholineacetyltransferasedecreasesbloodpressureinmurinehypertension
AT tynanaisling systemicadministrationofcholineacetyltransferasedecreasesbloodpressureinmurinehypertension
AT yanghuan systemicadministrationofcholineacetyltransferasedecreasesbloodpressureinmurinehypertension
AT tamariyehuda systemicadministrationofcholineacetyltransferasedecreasesbloodpressureinmurinehypertension
AT brinesmichael systemicadministrationofcholineacetyltransferasedecreasesbloodpressureinmurinehypertension
AT traceykevinj systemicadministrationofcholineacetyltransferasedecreasesbloodpressureinmurinehypertension
AT chavansangeetas systemicadministrationofcholineacetyltransferasedecreasesbloodpressureinmurinehypertension