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Cardiovascular Research Advance Access first published online on December 16, 2008
This version [Corrected Proof] published online on January 10, 2009
Cardiovascular Research, doi:10.1093/cvr/cvn349
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.
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Activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction

Angel Cogolludo1,2,{dagger}, Laura Moreno1,2,{dagger}, Giovanna Frazziano1,2, Javier Moral-Sanz1,2, Carmen Menendez1,2, Javier Castañeda3, Constancio González2,4, Eduardo Villamor5 and Francisco Perez-Vizcaino1,2,*

1 Department of Pharmacology, School of Medicine, University Complutense of Madrid, 28040 Madrid, Spain
2 Ciber Enfermedades Respiratorias, Ciberes, Spain
3 Department of Surgery, Intensive Care Unit, University Hospital of Valladolid, Valladolid, Spain
4 Department of Physiology, University of Valladolid, Valladolid, Spain
5 Department of Paediatrics, School for Oncology and Developmental Biology (GROW), Maastricht University Medical Centre (MUMC+), Maastricht, the Netherlands

* Corresponding author. Tel: +34 913941477; fax: +34 913941464. E-mail address: fperez{at}med.ucm.es

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 {zeta} (PKC{zeta}) and neutral sphingomyelinase (nSMase) in HPV.

Methods and results: Ceramide content was measured by immunocytochemistry and voltage-gated potassium channel (KV) 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 KV currents were strongly reduced by inhibition of PKC{zeta} 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 PKC{zeta} are early and necessary events in the signalling cascade of acute HPV.

KEYWORDS Hypoxic pulmonary vasoconstriction; Neutral sphingomyelinase; Protein kinase C {zeta}; Pulmonary arteries

Time for primary review: 30 days

{dagger} Both authors contributed equally.


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