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Cardiovascular Research Advance Access [Accepted Manuscript] published online on August 5, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn209
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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

Role of src-family kinases in hypoxic vasoconstriction of rat pulmonary artery

Greg A. Knock1, Vladimir A. Snetkov, Yasin Shaifta, Svetlana Drndarski, Jeremy P.T. Ward and Philip I. Aaronson

King's College London, Department of Asthma, Allergy and Respiratory Science, School of Medicine, Stamford Street, London SE1 9NH, UK

1 Corresponding author: Greg Knock, PhD, King's College London, Room 3.20, Franklin Wilkins Building, Stamford Street, London SE1 9NH, United Kingdom, tel: +44 020 7848 4297 fax: +44 020 7848 3743 greg.knock{at}kcl.ac.uk

Aims: We investigated the role of src-family kinases (srcFK) in hypoxic pulmonary vasoconstriction (HPV) and how this relates to Rho-kinase-mediated Ca2+ sensitization and changes in intracellular Ca2+ concentration ([Ca2+]i).

Methods: Intrapulmonary arteries (IPAs) were obtained from male Wistar rats. HPV was induced in myograph-mounted IPAs. Auto-phosphorylation of srcFK and phosphorylation of the regulatory subunit of myosin phosphatase (MYPT-1) and myosin light-chain (MLC20) in response to hypoxia were determined by Western blotting. Translocation of Rho-kinase and effects of siRNA knockdown of src and fyn were examined in cultured pulmonary artery smooth muscle cells (PASMC). [Ca2+]i was estimated in fura-PE3-loaded IPA.

Results: HPV was inhibited by two blockers of srcFK, SU6656 and PP2. Hypoxia enhanced phosphorylation of three srcFK proteins at Tyr-416 (60 kDa, 59 kDa and 54 kDa, corresponding to src, fyn and yes respectively) and enhanced srcFK-dependent tyrosine phosphorylation of multiple target proteins. Hypoxia caused a complex, time-dependent enhancement of MYPT-1 and MLC20 phosphorylation, both in the absence and presence of pre-constriction. The sustained component of this enhancement was blocked by SU6656 and the Rho-kinase inhibitor Y27632. In PASMC, hypoxia caused translocation of Rho-kinase from the nucleus to the cytoplasm, and this was prevented by anti-src siRNA and to a lesser extent by anti-fyn siRNA. The biphasic increases in [Ca2+]i that accompany HPV were also inhibited by PP2.

Conclusions: Hypoxia activates srcFK and triggers protein tyrosine phosphorylation in IPA. Hypoxia-mediated Rho-kinase activation, Ca2+ sensitization and [Ca2+]i responses are depressed by srcFK inhibitors and/or siRNA knockdown, suggesting a central role for srcFK in HPV.

Time for primary review: 28 Days


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