Cargando…

Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in K(Ca)2.3 and K(Ca)3.1 Channels

OBJECTIVE: In vascular biology, endothelial K(Ca)2.3 and K(Ca)3.1 channels contribute to arterial blood pressure regulation by producing membrane hyperpolarization and smooth muscle relaxation. The role of K(Ca)2.3 and K(Ca)3.1 channels in the pulmonary circulation is not fully established. Using mi...

Descripción completa

Detalles Bibliográficos
Autores principales: Wandall-Frostholm, Christine, Skaarup, Lykke Moran, Sadda, Veeranjaneyulu, Nielsen, Gorm, Hedegaard, Elise Røge, Mogensen, Susie, Köhler, Ralf, Simonsen, Ulf
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032241/
https://www.ncbi.nlm.nih.gov/pubmed/24858807
http://dx.doi.org/10.1371/journal.pone.0097687
_version_ 1782317613431390208
author Wandall-Frostholm, Christine
Skaarup, Lykke Moran
Sadda, Veeranjaneyulu
Nielsen, Gorm
Hedegaard, Elise Røge
Mogensen, Susie
Köhler, Ralf
Simonsen, Ulf
author_facet Wandall-Frostholm, Christine
Skaarup, Lykke Moran
Sadda, Veeranjaneyulu
Nielsen, Gorm
Hedegaard, Elise Røge
Mogensen, Susie
Köhler, Ralf
Simonsen, Ulf
author_sort Wandall-Frostholm, Christine
collection PubMed
description OBJECTIVE: In vascular biology, endothelial K(Ca)2.3 and K(Ca)3.1 channels contribute to arterial blood pressure regulation by producing membrane hyperpolarization and smooth muscle relaxation. The role of K(Ca)2.3 and K(Ca)3.1 channels in the pulmonary circulation is not fully established. Using mice with genetically encoded deficit of K(Ca)2.3 and K(Ca)3.1 channels, this study investigated the effect of loss of the channels in hypoxia-induced pulmonary hypertension. APPROACH AND RESULT: Male wild type and K(Ca)3.1(−/−)/K(Ca)2.3(T/T(+DOX)) mice were exposed to chronic hypoxia for four weeks to induce pulmonary hypertension. The degree of pulmonary hypertension was evaluated by right ventricular pressure and assessment of right ventricular hypertrophy. Segments of pulmonary arteries were mounted in a wire myograph for functional studies and morphometric studies were performed on lung sections. Chronic hypoxia induced pulmonary hypertension, right ventricular hypertrophy, increased lung weight, and increased hematocrit levels in either genotype. The K(Ca)3.1(−/−)/K(Ca)2.3(T/T(+DOX)) mice developed structural alterations in the heart with increased right ventricular wall thickness as well as in pulmonary vessels with increased lumen size in partially- and fully-muscularized vessels and decreased wall area, not seen in wild type mice. Exposure to chronic hypoxia up-regulated the gene expression of the K(Ca)2.3 channel by twofold in wild type mice and increased by 2.5-fold the relaxation evoked by the K(Ca)2.3 and K(Ca)3.1 channel activator NS309, whereas the acetylcholine-induced relaxation - sensitive to the combination of K(Ca)2.3 and K(Ca)3.1 channel blockers, apamin and charybdotoxin - was reduced by 2.5-fold in chronic hypoxic mice of either genotype. CONCLUSION: Despite the deficits of the K(Ca)2.3 and K(Ca)3.1 channels failed to change hypoxia-induced pulmonary hypertension, the up-regulation of K(Ca)2.3-gene expression and increased NS309-induced relaxation in wild-type mice point to a novel mechanism to counteract pulmonary hypertension and to a potential therapeutic utility of K(Ca)2.3/K(Ca)3.1 activators for the treatment of pulmonary hypertension.
format Online
Article
Text
id pubmed-4032241
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-40322412014-05-28 Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in K(Ca)2.3 and K(Ca)3.1 Channels Wandall-Frostholm, Christine Skaarup, Lykke Moran Sadda, Veeranjaneyulu Nielsen, Gorm Hedegaard, Elise Røge Mogensen, Susie Köhler, Ralf Simonsen, Ulf PLoS One Research Article OBJECTIVE: In vascular biology, endothelial K(Ca)2.3 and K(Ca)3.1 channels contribute to arterial blood pressure regulation by producing membrane hyperpolarization and smooth muscle relaxation. The role of K(Ca)2.3 and K(Ca)3.1 channels in the pulmonary circulation is not fully established. Using mice with genetically encoded deficit of K(Ca)2.3 and K(Ca)3.1 channels, this study investigated the effect of loss of the channels in hypoxia-induced pulmonary hypertension. APPROACH AND RESULT: Male wild type and K(Ca)3.1(−/−)/K(Ca)2.3(T/T(+DOX)) mice were exposed to chronic hypoxia for four weeks to induce pulmonary hypertension. The degree of pulmonary hypertension was evaluated by right ventricular pressure and assessment of right ventricular hypertrophy. Segments of pulmonary arteries were mounted in a wire myograph for functional studies and morphometric studies were performed on lung sections. Chronic hypoxia induced pulmonary hypertension, right ventricular hypertrophy, increased lung weight, and increased hematocrit levels in either genotype. The K(Ca)3.1(−/−)/K(Ca)2.3(T/T(+DOX)) mice developed structural alterations in the heart with increased right ventricular wall thickness as well as in pulmonary vessels with increased lumen size in partially- and fully-muscularized vessels and decreased wall area, not seen in wild type mice. Exposure to chronic hypoxia up-regulated the gene expression of the K(Ca)2.3 channel by twofold in wild type mice and increased by 2.5-fold the relaxation evoked by the K(Ca)2.3 and K(Ca)3.1 channel activator NS309, whereas the acetylcholine-induced relaxation - sensitive to the combination of K(Ca)2.3 and K(Ca)3.1 channel blockers, apamin and charybdotoxin - was reduced by 2.5-fold in chronic hypoxic mice of either genotype. CONCLUSION: Despite the deficits of the K(Ca)2.3 and K(Ca)3.1 channels failed to change hypoxia-induced pulmonary hypertension, the up-regulation of K(Ca)2.3-gene expression and increased NS309-induced relaxation in wild-type mice point to a novel mechanism to counteract pulmonary hypertension and to a potential therapeutic utility of K(Ca)2.3/K(Ca)3.1 activators for the treatment of pulmonary hypertension. Public Library of Science 2014-05-23 /pmc/articles/PMC4032241/ /pubmed/24858807 http://dx.doi.org/10.1371/journal.pone.0097687 Text en © 2014 Wandall-Frostholm et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Wandall-Frostholm, Christine
Skaarup, Lykke Moran
Sadda, Veeranjaneyulu
Nielsen, Gorm
Hedegaard, Elise Røge
Mogensen, Susie
Köhler, Ralf
Simonsen, Ulf
Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in K(Ca)2.3 and K(Ca)3.1 Channels
title Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in K(Ca)2.3 and K(Ca)3.1 Channels
title_full Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in K(Ca)2.3 and K(Ca)3.1 Channels
title_fullStr Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in K(Ca)2.3 and K(Ca)3.1 Channels
title_full_unstemmed Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in K(Ca)2.3 and K(Ca)3.1 Channels
title_short Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in K(Ca)2.3 and K(Ca)3.1 Channels
title_sort pulmonary hypertension in wild type mice and animals with genetic deficit in k(ca)2.3 and k(ca)3.1 channels
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032241/
https://www.ncbi.nlm.nih.gov/pubmed/24858807
http://dx.doi.org/10.1371/journal.pone.0097687
work_keys_str_mv AT wandallfrostholmchristine pulmonaryhypertensioninwildtypemiceandanimalswithgeneticdeficitinkca23andkca31channels
AT skaaruplykkemoran pulmonaryhypertensioninwildtypemiceandanimalswithgeneticdeficitinkca23andkca31channels
AT saddaveeranjaneyulu pulmonaryhypertensioninwildtypemiceandanimalswithgeneticdeficitinkca23andkca31channels
AT nielsengorm pulmonaryhypertensioninwildtypemiceandanimalswithgeneticdeficitinkca23andkca31channels
AT hedegaardeliserøge pulmonaryhypertensioninwildtypemiceandanimalswithgeneticdeficitinkca23andkca31channels
AT mogensensusie pulmonaryhypertensioninwildtypemiceandanimalswithgeneticdeficitinkca23andkca31channels
AT kohlerralf pulmonaryhypertensioninwildtypemiceandanimalswithgeneticdeficitinkca23andkca31channels
AT simonsenulf pulmonaryhypertensioninwildtypemiceandanimalswithgeneticdeficitinkca23andkca31channels