Interaction between src family kinases and rho-kinase in agonist-induced Ca2+-sensitization of rat pulmonary artery

Knock, G.A., Shaifta, Y., Snetkov, V.A., Vowles, B., Drndarski, S., Ward, J.P. and Aaronson, P.I. 2008. Interaction between src family kinases and rho-kinase in agonist-induced Ca2+-sensitization of rat pulmonary artery. Cardiovascular Research. 77 (3), pp. 570-9. https://doi.org/10.1093/cvr/cvm073

TitleInteraction between src family kinases and rho-kinase in agonist-induced Ca2+-sensitization of rat pulmonary artery
TypeJournal article
AuthorsKnock, G.A., Shaifta, Y., Snetkov, V.A., Vowles, B., Drndarski, S., Ward, J.P. and Aaronson, P.I.
Abstract

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 and results: Intra-pulmonary arteries (IPAs) 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 F(2 alpha) (PGF(2 alpha)) in alpha-toxin-permeabilized IPAs. 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 PGF(2 alpha) were also determined. Nine srcFK were expressed at the mRNA level, including src, fyn, and yes, and PGF(2 alpha) enhanced phosphorylation of three srcFK proteins at tyr-416. In alpha-toxin-permeabilized IPAs, PGF(2 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. PGF(2 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 PGF(2 alpha)-mediated phosphorylation. The effects of SU6656 and Y27632, on both contraction and MYPT-1 and MLC20 phosphorylation, were not additive. PGF(2 alpha) triggered translocation of rho-kinase in PASMC, and this was inhibited by SU6656.

Conclusions: srcFK are activated by PGF(2 alpha) in the rat pulmonary artery and may contribute to Ca2+-sensitization and contraction via rho-kinase translocation and phosphorylation of MYPT-1.

KeywordsPulmonary circulation
Vasoconstriction/dilation
Tyrosine
Protein kinases
Prostaglandins
Rho-kinase
JournalCardiovascular Research
Journal citation77 (3), pp. 570-9
ISSN0008-6363
Year2008
PublisherOxford Academic
Publisher's version
File Access Level
Open (open metadata and files)
Digital Object Identifier (DOI)https://doi.org/10.1093/cvr/cvm073
PubMed ID18032393
Web address (URL)https://academic.oup.com/cardiovascres/article/77/3/570/509167
Publication dates
Published01 Feb 2008
Published online21 Nov 2007

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