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Cardiovascular Research Advance Access [Accepted Manuscript] published online on December 16, 2008
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 2008. For permissions please email: journals.permissions@oxfordjournals.org.
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.

Activation of neutral sphingomyelinase is involved in acute hypoxic pulmonary vasoconstriction

Angel Cogolludoa,b,*, Laura Morenoa,b,*, Giovanna Frazzianoa,b, Javier Moral-Sanza,b, Carmen Menendeza,b, Javier Castañedac, Constancio Gonzálezb,d, Eduardo Villamore and Francisco Perez-Vizcainoa,b

a Department of Pharmacology, School of Medicine, University Complutense of Madrid, 28040 Madrid, Spain
b Ciber Enfermedades Respiratorias (Ciberes). Spain
c Department of Surgery, Intensive Care Unit, University Hospital of Valladolid, Spain
d Department of Physiology, University of Valladolid. Spain
e Department of Paediatrics, Maastricht University Medical Centre (MUMC + ), School for Oncology and Developmental Biology (GROW), Maastricht, the Netherlands

Author for correspondence: F. Perez-Vizcaino. Departamento de Farmacología, Facultad de Medicina, Universidad Complutense Madrid. 28040 Madrid. Spain. Tel: 34-913941477. Fax: 34-913941464. email: 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: 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 cells (PASMC). Contractile responses were analyzed 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.

Results: 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. nSMase2 mRNA expression was ~10 fold higher in pulmonary compared to mesenteric arteries. In mesenteric arteries, hypoxia failed to increase ceramide but exogenous SMase induced a contractile response.

Conclusions: nSMase-derived ceramide production and the activation of PKC{zeta} are early and necessary events in the signaling cascade of acute HPV.

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

Time for primary review: 30 Days

* Both authors contributed equally.


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