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Br J Pharmacol. 2014 May;171(9):2413-25. doi: 10.1111/bph.12593.

Proteinase-activated receptors 1 and 2 and the regulation of porcine coronary artery contractility: a role for distinct tyrosine kinase pathways.

Author information

1
Libin Cardiovascular Institute of Alberta and the Snyder Institute for Chronic Diseases, Calgary, AB, Canada; Department of Physiology and Pharmacology, The University of Calgary Faculty of Medicine, Calgary, AB, Canada.

Abstract

BACKGROUND AND PURPOSE:

Because angiotensin-II-mediated porcine coronary artery (PCA) vasoconstriction is blocked by protein tyrosine kinase (PYK) inhibitors, we hypothesized that proteinase-activated receptors (PARs), known to regulate vascular tension, like angiotensin-II, would also cause PCA contractions via PYK-dependent signalling pathways.

EXPERIMENTAL APPROACH:

Contractions of intact and endothelium-free isolated PCA rings, stimulated by PAR1 /PAR2 -activating peptides, angiotensin-II, PGF2α , EGF, PDGF and KCl, were monitored with/without multiple signalling pathway inhibitors, including AG-tyrphostins AG18 (non-specific PYKs), AG1478 (EGF-receptor kinase), AG1296 (PDGF receptor kinase), PP1 (Src kinase), U0126 and PD98059 (MEK/MAPKinase kinase), indomethacin/SC-560/NS-398 (COX-1/2) and L-NAME (NOS).

KEY RESULTS:

AG18 inhibited the contractions induced by all the agonists except KCl, whereas U0126 attenuated contractions induced by PAR1 /PAR2 agonists, EGF and angiotensin-II, but not by PGF2α , the COX-produced metabolites of arachidonate and KCl. PP1 only affected the responses to PAR1 /PAR2 -activating peptides and angiotensin-II. The EGF-kinase inhibitor, AG1478, attenuated contractions initiated by the PARs (PAR2 >> PAR1 ) and EGF itself, but not by angiotensin-II, PGF2α or KCl. COX-1/2 inhibitors blocked the contractions induced by all the agonists, except KCl and PGF2α .

CONCLUSION AND IMPLICATIONS:

PAR1/2 -mediated contractions of the PCA are dependent on Src and MAPKinase and, in part, involve EGF-receptor-kinase transactivation and the generation of a COX-derived contractile agonist. However, the PYK signalling pathways used by PARs are distinct from each other and from those triggered by angiotensin-II and EGF. These signalling pathways may be therapeutic targets for managing coagulation-proteinase-induced coronary vasospasm.

KEYWORDS:

EGF; MAPKinase; PARs; PGF2α; angiotensin-II; coronary contraction; cyclooxygenase; protease; proteinase-activated receptors; tyrosine kinase signalling pathways

PMID:
24506284
PMCID:
PMC3997280
DOI:
10.1111/bph.12593
[Indexed for MEDLINE]
Free PMC Article

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