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Cardiovascular Research Advance Access [Accepted Manuscript] published online on November 21, 2007
Cardiovascular Research, doi:10.1093/cvr/cvm073
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Interaction Between Src-Family Kinases and Rho-Kinase in Agonist-Induced Ca2+-Sensitization of Rat Pulmonary Artery

Greg A. Knock1, Yasin Shaifta, Vladimir A. Snetkov, Benjamin Vowles, 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 agonist-mediated Ca2+-sensitization in pulmonary artery, and whether this involves interaction with the Rho/Rho-kinase pathway.

Methods: Intra-pulmonary arteries (IPA) and cultured pulmonary artery smooth muscle cells (PASMC) were obtained from rat. Expression of srcFK was determined at the mRNA and protein levels. Ca2+-sensitization was induced by prostaglandin F2{alpha} (PGF2{alpha}) in {alpha}-toxin permeabilised IPA. Phosphorylation of the regulatory subunit of myosin phosphatase (MYPT-1) and of myosin light-chain-20 (MLC20) and translocation of Rho-kinase in response to PGF2{alpha} was also determined.

Results: Nine srcFK were expressed at the mRNA level, including src, fyn and yes and PGF2{alpha} enhanced phosphorylation of three srcFK proteins at tyr-416. In {alpha}-toxin permeabilised IPA, PGF2{alpha} enhanced the Ca2+-induced contraction (pCa 6.9) approximately three-fold. This enhancement was inhibited by the srcFK blockers SU6656 and PP2, and by the Rho-kinase inhibitor Y27632. Y27632, but not SU6656 or PP2, also inhibited the underlying pCa 6.9 contraction. PGF2{alpha} enhanced phosphorylation of MYPT-1 at thr-697 and thr-855 and of MLC20 at ser-19. This enhancement, but not the underlying basal phosphorylation was inhibited by SU6656. Y27632 suppressed both basal and PGF2{alpha}-mediated phosphorylation. The effects of SU6656 and Y27632, on both contraction and MYPT-1 and MLC20 phosphorylation, were not additive. PGF2{alpha} triggered translocation of Rho-kinase in pulmonary artery smooth muscle cells and this was inhibited by SU6656.

Conclusions: srcFK are activated by PGF2{alpha} in the rat pulmonary artery and may contribute to Ca2+-sensitization and contraction via Rho-kinase translocation and phosphorylation of MYPT-1.

Time for primary review: 34


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