Role of SRC-Family Kinases in Hypoxic Vasoconstriction of Rat Pulmonary Artery

Knock, G.A., Snetkov, V.A., Shaifta, Y., Drndarski, S., Ward, J.P. and Aaronson, P.I. 2008. Role of SRC-Family Kinases in Hypoxic Vasoconstriction of Rat Pulmonary Artery. Cardiovascular Research. 80 (3), pp. 453-62. https://doi.org/10.1093/cvr/cvn209

TitleRole of SRC-Family Kinases in Hypoxic Vasoconstriction of Rat Pulmonary Artery
TypeJournal article
AuthorsKnock, G.A., Snetkov, V.A., Shaifta, Y., Drndarski, S., Ward, J.P. and Aaronson, P.I.
Abstract

Aims: We investigated the role of src-family kinases (srcFKs) in hypoxic pulmonary vasoconstriction (HPV) and how this relates to Rho-kinase-mediated Ca(2+) sensitization and changes in intracellular Ca(2+) concentration ([Ca(2+)](i)).

Methods and results: Intra-pulmonary arteries (IPAs) were obtained from male Wistar rats. HPV was induced in myograph-mounted IPAs. Auto-phosphorylation of srcFKs and phosphorylation of the regulatory subunit of myosin phosphatase (MYPT-1) and myosin light-chain (MLC(20)) 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 (PASMCs). [Ca(2+)](i) was estimated in Fura-PE3-loaded IPA. HPV was inhibited by two blockers of srcFKs, SU6656 and PP2. Hypoxia enhanced phosphorylation of three srcFK proteins at Tyr-416 (60, 59, 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 MLC(20) 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 PASMCs, 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 [Ca(2+)](i) that accompany HPV were also inhibited by PP2.

Conclusion: Hypoxia activates srcFKs and triggers protein tyrosine phosphorylation in IPA. Hypoxia-mediated Rho-kinase activation, Ca(2+) sensitization, and [Ca(2+)](i) responses are depressed by srcFK inhibitors and/or siRNA knockdown, suggesting a central role of srcFKs in HPV.

KeywordsHypoxia
Tyrosine kinase
src-family kinase
Rho-kinase
Pulmonary
Vasoconstriction
JournalCardiovascular Research
Journal citation80 (3), pp. 453-62
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/cvn209
PubMed ID18682436
Web address (URL)https://academic.oup.com/cardiovascres/article/80/3/453/322532
Publication dates
Published01 Dec 2008
Published in print05 Aug 2008

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