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Acute inhibition of PMCA4, but not global ablation, reduces blood pressure and arterial contractility via a nNOS‐dependent mechanism

Cardiovascular disease is the world's leading cause of morbidity and mortality, with high blood pressure (BP) contributing to increased severity and number of adverse outcomes. Plasma membrane calcium ATPase 4 (PMCA4) has been previously shown to modulate systemic BP. However, published data ar...

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Autores principales: Lewis, Sophronia, Little, Robert, Baudoin, Florence, Prehar, Sukhpal, Neyses, Ludwig, Cartwright, Elizabeth J., Austin, Clare
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783868/
https://www.ncbi.nlm.nih.gov/pubmed/29193716
http://dx.doi.org/10.1111/jcmm.13371
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author Lewis, Sophronia
Little, Robert
Baudoin, Florence
Prehar, Sukhpal
Neyses, Ludwig
Cartwright, Elizabeth J.
Austin, Clare
author_facet Lewis, Sophronia
Little, Robert
Baudoin, Florence
Prehar, Sukhpal
Neyses, Ludwig
Cartwright, Elizabeth J.
Austin, Clare
author_sort Lewis, Sophronia
collection PubMed
description Cardiovascular disease is the world's leading cause of morbidity and mortality, with high blood pressure (BP) contributing to increased severity and number of adverse outcomes. Plasma membrane calcium ATPase 4 (PMCA4) has been previously shown to modulate systemic BP. However, published data are conflicting, with both overexpression and inhibition of PMCA4 in vivo shown to increase arterial contractility. Hence, our objective was to determine the role of PMCA4 in the regulation of BP and to further understand how PMCA4 functionally regulates BP using a novel specific inhibitor to PMCA4, aurintricarboxylic acid (ATA). Our approach assessed conscious BP and contractility of resistance arteries from PMCA4 global knockout (PMCA4KO) mice compared to wild‐type animals. Global ablation of PMCA4 had no significant effect on BP, arterial structure or isolated arterial contractility. ATA treatment significantly reduced BP and arterial contractility in wild‐type mice but had no significant effect in PMCA4KO mice. The effect of ATA in vivo and ex vivo was abolished by the neuronal nitric oxide synthase (nNOS) inhibitor Vinyl‐l‐NIO. Thus, this highlights differences in the effects of PMCA4 ablation and acute inhibition on the vasculature. Importantly, for doses here used, we show the vascular effects of ATA to be specific for PMCA4 and that ATA may be a further experimental tool for elucidating the role of PMCA4.
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spelling pubmed-57838682018-02-08 Acute inhibition of PMCA4, but not global ablation, reduces blood pressure and arterial contractility via a nNOS‐dependent mechanism Lewis, Sophronia Little, Robert Baudoin, Florence Prehar, Sukhpal Neyses, Ludwig Cartwright, Elizabeth J. Austin, Clare J Cell Mol Med Original Articles Cardiovascular disease is the world's leading cause of morbidity and mortality, with high blood pressure (BP) contributing to increased severity and number of adverse outcomes. Plasma membrane calcium ATPase 4 (PMCA4) has been previously shown to modulate systemic BP. However, published data are conflicting, with both overexpression and inhibition of PMCA4 in vivo shown to increase arterial contractility. Hence, our objective was to determine the role of PMCA4 in the regulation of BP and to further understand how PMCA4 functionally regulates BP using a novel specific inhibitor to PMCA4, aurintricarboxylic acid (ATA). Our approach assessed conscious BP and contractility of resistance arteries from PMCA4 global knockout (PMCA4KO) mice compared to wild‐type animals. Global ablation of PMCA4 had no significant effect on BP, arterial structure or isolated arterial contractility. ATA treatment significantly reduced BP and arterial contractility in wild‐type mice but had no significant effect in PMCA4KO mice. The effect of ATA in vivo and ex vivo was abolished by the neuronal nitric oxide synthase (nNOS) inhibitor Vinyl‐l‐NIO. Thus, this highlights differences in the effects of PMCA4 ablation and acute inhibition on the vasculature. Importantly, for doses here used, we show the vascular effects of ATA to be specific for PMCA4 and that ATA may be a further experimental tool for elucidating the role of PMCA4. John Wiley and Sons Inc. 2017-11-30 2018-02 /pmc/articles/PMC5783868/ /pubmed/29193716 http://dx.doi.org/10.1111/jcmm.13371 Text en © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Lewis, Sophronia
Little, Robert
Baudoin, Florence
Prehar, Sukhpal
Neyses, Ludwig
Cartwright, Elizabeth J.
Austin, Clare
Acute inhibition of PMCA4, but not global ablation, reduces blood pressure and arterial contractility via a nNOS‐dependent mechanism
title Acute inhibition of PMCA4, but not global ablation, reduces blood pressure and arterial contractility via a nNOS‐dependent mechanism
title_full Acute inhibition of PMCA4, but not global ablation, reduces blood pressure and arterial contractility via a nNOS‐dependent mechanism
title_fullStr Acute inhibition of PMCA4, but not global ablation, reduces blood pressure and arterial contractility via a nNOS‐dependent mechanism
title_full_unstemmed Acute inhibition of PMCA4, but not global ablation, reduces blood pressure and arterial contractility via a nNOS‐dependent mechanism
title_short Acute inhibition of PMCA4, but not global ablation, reduces blood pressure and arterial contractility via a nNOS‐dependent mechanism
title_sort acute inhibition of pmca4, but not global ablation, reduces blood pressure and arterial contractility via a nnos‐dependent mechanism
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783868/
https://www.ncbi.nlm.nih.gov/pubmed/29193716
http://dx.doi.org/10.1111/jcmm.13371
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