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

C. Wandall-Frostholm, L. M. Skaarup, Veeranjaneyulu Sadda, Gorm Nielsen, E. R. Hedegaard, S. Mogensen, Ralf Köhler, U. Simonsen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.
OriginalsprogEngelsk
Artikelnummere97687
TidsskriftP L o S One
Vol/bind9
Udgave nummer5
Antal sider11
ISSN1932-6203
DOI
StatusUdgivet - 2014

Citer dette

Wandall-Frostholm, C., Skaarup, L. M., Sadda, V., Nielsen, G., Hedegaard, E. R., Mogensen, S., ... Simonsen, U. (2014). Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in K(Ca)2.3 and K(Ca)3.1 Channels. P L o S One, 9(5), [e97687]. https://doi.org/10.1371/journal.pone.0097687
Wandall-Frostholm, C. ; Skaarup, L. M. ; Sadda, Veeranjaneyulu ; Nielsen, Gorm ; Hedegaard, E. R. ; Mogensen, S. ; Köhler, Ralf ; Simonsen, U. / Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in K(Ca)2.3 and K(Ca)3.1 Channels. I: P L o S One. 2014 ; Bind 9, Nr. 5.
@article{6fe8221b61274eb2bf269dc47a519d77,
title = "Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in K(Ca)2.3 and K(Ca)3.1 Channels",
abstract = "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.",
author = "C. Wandall-Frostholm and Skaarup, {L. M.} and Veeranjaneyulu Sadda and Gorm Nielsen and Hedegaard, {E. R.} and S. Mogensen and Ralf K{\"o}hler and U. Simonsen",
year = "2014",
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language = "English",
volume = "9",
journal = "P L o S One",
issn = "1932-6203",
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Wandall-Frostholm, C, Skaarup, LM, Sadda, V, Nielsen, G, Hedegaard, ER, Mogensen, S, Köhler, R & Simonsen, U 2014, 'Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in K(Ca)2.3 and K(Ca)3.1 Channels', P L o S One, bind 9, nr. 5, e97687. https://doi.org/10.1371/journal.pone.0097687

Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in K(Ca)2.3 and K(Ca)3.1 Channels. / Wandall-Frostholm, C.; Skaarup, L. M.; Sadda, Veeranjaneyulu; Nielsen, Gorm; Hedegaard, E. R.; Mogensen, S.; Köhler, Ralf; Simonsen, U.

I: P L o S One, Bind 9, Nr. 5, e97687, 2014.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in K(Ca)2.3 and K(Ca)3.1 Channels

AU - Wandall-Frostholm, C.

AU - Skaarup, L. M.

AU - Sadda, Veeranjaneyulu

AU - Nielsen, Gorm

AU - Hedegaard, E. R.

AU - Mogensen, S.

AU - Köhler, Ralf

AU - Simonsen, U.

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pone.0097687

DO - 10.1371/journal.pone.0097687

M3 - Journal article

C2 - 24858807

VL - 9

JO - P L o S One

JF - P L o S One

SN - 1932-6203

IS - 5

M1 - e97687

ER -

Wandall-Frostholm C, Skaarup LM, Sadda V, Nielsen G, Hedegaard ER, Mogensen S et al. Pulmonary Hypertension in Wild Type Mice and Animals with Genetic Deficit in K(Ca)2.3 and K(Ca)3.1 Channels. P L o S One. 2014;9(5). e97687. https://doi.org/10.1371/journal.pone.0097687