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Activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction

AIMS: The mechanisms involved in hypoxic pulmonary vasoconstriction (HPV) are not yet fully defined. The aim of the study was to determine the role of protein kinase C ζ (PKCζ) and neutral sphingomyelinase (nSMase) in HPV. METHODS AND RESULTS: Ceramide content was measured by immunocytochemistry and...

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Autores principales: Cogolludo, Angel, Moreno, Laura, Frazziano, Giovanna, Moral-Sanz, Javier, Menendez, Carmen, Castañeda, Javier, González, Constancio, Villamor, Eduardo, Perez-Vizcaino, Francisco
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2675929/
https://www.ncbi.nlm.nih.gov/pubmed/19088082
http://dx.doi.org/10.1093/cvr/cvn349
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author Cogolludo, Angel
Moreno, Laura
Frazziano, Giovanna
Moral-Sanz, Javier
Menendez, Carmen
Castañeda, Javier
González, Constancio
Villamor, Eduardo
Perez-Vizcaino, Francisco
author_facet Cogolludo, Angel
Moreno, Laura
Frazziano, Giovanna
Moral-Sanz, Javier
Menendez, Carmen
Castañeda, Javier
González, Constancio
Villamor, Eduardo
Perez-Vizcaino, Francisco
author_sort Cogolludo, Angel
collection PubMed
description AIMS: The mechanisms involved in hypoxic pulmonary vasoconstriction (HPV) are not yet fully defined. The aim of the study was to determine the role of protein kinase C ζ (PKCζ) and neutral sphingomyelinase (nSMase) in HPV. METHODS AND RESULTS: Ceramide content was measured by immunocytochemistry and voltage-gated potassium channel (K(V)) currents were recorded by the patch clamp technique in isolated rat pulmonary artery smooth muscle cells (PASMC). Contractile responses were analysed in rat pulmonary arteries mounted in a wire myograph. Pulmonary pressure was recorded in anesthetized open-chest rats. Protein and mRNA expression were measured by western blot and RT–PCR, respectively. We found that hypoxia increased ceramide content in PASMC which was abrogated by inhibition of nSMase, but not acid sphingomyelinase (aSMase). The hypoxia-induced vasoconstrictor response in isolated pulmonary arteries and the inhibition of K(V) currents were strongly reduced by inhibition of PKCζ or nSMase but not aSMase. The nSMase inhibitor GW4869 prevented HPV in vivo. The vasoconstrictor response to hypoxia was mimicked by exogenous addition of bacterial Smase and ceramide. nSMase2 mRNA expression was ∼10-fold higher in pulmonary compared with mesenteric arteries. In mesenteric arteries, hypoxia failed to increase ceramide but exogenous SMase induced a contractile response. CONCLUSION: nSMase-derived ceramide production and the activation of PKCζ are early and necessary events in the signalling cascade of acute HPV.
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spelling pubmed-26759292009-07-01 Activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction Cogolludo, Angel Moreno, Laura Frazziano, Giovanna Moral-Sanz, Javier Menendez, Carmen Castañeda, Javier González, Constancio Villamor, Eduardo Perez-Vizcaino, Francisco Cardiovasc Res Original Articles AIMS: The mechanisms involved in hypoxic pulmonary vasoconstriction (HPV) are not yet fully defined. The aim of the study was to determine the role of protein kinase C ζ (PKCζ) and neutral sphingomyelinase (nSMase) in HPV. METHODS AND RESULTS: Ceramide content was measured by immunocytochemistry and voltage-gated potassium channel (K(V)) currents were recorded by the patch clamp technique in isolated rat pulmonary artery smooth muscle cells (PASMC). Contractile responses were analysed in rat pulmonary arteries mounted in a wire myograph. Pulmonary pressure was recorded in anesthetized open-chest rats. Protein and mRNA expression were measured by western blot and RT–PCR, respectively. We found that hypoxia increased ceramide content in PASMC which was abrogated by inhibition of nSMase, but not acid sphingomyelinase (aSMase). The hypoxia-induced vasoconstrictor response in isolated pulmonary arteries and the inhibition of K(V) currents were strongly reduced by inhibition of PKCζ or nSMase but not aSMase. The nSMase inhibitor GW4869 prevented HPV in vivo. The vasoconstrictor response to hypoxia was mimicked by exogenous addition of bacterial Smase and ceramide. nSMase2 mRNA expression was ∼10-fold higher in pulmonary compared with mesenteric arteries. In mesenteric arteries, hypoxia failed to increase ceramide but exogenous SMase induced a contractile response. CONCLUSION: nSMase-derived ceramide production and the activation of PKCζ are early and necessary events in the signalling cascade of acute HPV. Oxford University Press 2009-05-01 2008-12-16 /pmc/articles/PMC2675929/ /pubmed/19088082 http://dx.doi.org/10.1093/cvr/cvn349 Text en Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org. http://creativecommons.org/licenses/by-nc/2.0/uk/ The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that the original authorship is properly and fully attributed; the Journal, Learned Society and Oxford University Press are attributed as the original place of publication with correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org.
spellingShingle Original Articles
Cogolludo, Angel
Moreno, Laura
Frazziano, Giovanna
Moral-Sanz, Javier
Menendez, Carmen
Castañeda, Javier
González, Constancio
Villamor, Eduardo
Perez-Vizcaino, Francisco
Activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction
title Activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction
title_full Activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction
title_fullStr Activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction
title_full_unstemmed Activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction
title_short Activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction
title_sort activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2675929/
https://www.ncbi.nlm.nih.gov/pubmed/19088082
http://dx.doi.org/10.1093/cvr/cvn349
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