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UDP-sugars activate P2Y 14 receptors to mediate vasoconstriction of the porcine coronary artery

Abbas, Zainab S.B.; Latif, Muhammad Liaque; Dovlatova, Natalia; Fox, Sue C.; Heptinstall, Stan; Dunn, William R.; Ralevic, Vera

Authors

Zainab S.B. Abbas

Muhammad Liaque Latif

Natalia Dovlatova natalia.dovlatova@plateletsolutions.co.uk

Sue C. Fox

Stan Heptinstall

VERA RALEVIC vera.ralevic@nottingham.ac.uk
Associate Professor & Reader in Cardiovascular Sciences



Abstract

Aims

UDP-sugars can act as extracellular signalling molecules, but relatively little is known about their cardiovascular actions. The P2Y14 receptor is a Gi/o-coupled receptor which is activated by UDP-glucose and related sugar nucleotides. In this study we sought to investigate whether P2Y14 receptors are functionally expressed in the porcine coronary artery using a selective P2Y14 receptor agonist, MRS2690, and a novel selective P2Y14 receptor antagonist, PPTN (4,7-disubstituted naphthoic acid derivative).

Methods and results

Isometric tension recordings were used to evaluate the effects of UDP-sugars in porcine isolated coronary artery segments. The effects of the P2 receptor antagonists suramin and PPADS, the P2Y14 receptor antagonist PPTN, and the P2Y6 receptor antagonist MRS2578, were investigated. Measurement of vasodilator-stimulated phosphoprotein (VASP) phosphorylation using flow cytometry was used to assess changes in cAMP levels. UDP-glucose, UDP-glucuronic acid UDP-N-acetylglucosamine (P2Y14 receptor agonists), elicited concentration-dependent contractions in the porcine coronary artery. MRS2690 was a more potent vasoconstrictor than the UDP-sugars. Concentration dependent contractile responses to MRS2690 and UDP-sugars were enhanced in the presence of forskolin (activator of cAMP), where the level of basal tone was maintained by addition of U46619, a thromboxane A2 mimetic. Contractile responses to MRS2690 were blocked by PPTN, but not by MRS2578. Contractile responses to UDP-glucose were also attenuated by PPTN and suramin, but not by MRS2578. Forskolin-induced VASP-phosphorylation was reduced in porcine coronary arteries exposed to UDP-glucose and MRS2690, consistent with P2Y14 receptor coupling to Gi/o proteins and inhibition of adenylyl cyclase activity.

Conclusions

Our data support a role of UDP-sugars as extracellular signalling molecules and show for the first time that they mediate contraction of porcine coronary arteries via P2Y14 receptors.

Citation

Abbas, Z. S., Latif, M. L., Dovlatova, N., Fox, S. C., Heptinstall, S., Dunn, W. R., & Ralevic, V. (2018). UDP-sugars activate P2Y 14 receptors to mediate vasoconstriction of the porcine coronary artery. Vascular Pharmacology, 103-105, https://doi.org/10.1016/j.vph.2017.12.063

Journal Article Type Article
Acceptance Date Dec 12, 2017
Online Publication Date Dec 15, 2017
Publication Date Apr 30, 2018
Deposit Date Jan 9, 2018
Publicly Available Date Jan 9, 2018
Journal Vascular Pharmacology
Print ISSN 1537-1891
Electronic ISSN 1879-3649
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 103-105
DOI https://doi.org/10.1016/j.vph.2017.12.063
Keywords Coronary artery; P2Y6 receptor; P2Y14 receptor; UDP-glucose; UDP sugars; MRS2690; Sugar nucleotides
Public URL http://eprints.nottingham.ac.uk/id/eprint/48996
Publisher URL https://doi.org/10.1016/j.vph.2017.12.063
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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