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

Mahmoud El-Daly, Mahmoud Saifeddine, Koichiro Mihara, Rithwik Ramachandran, Christopher R. Triggle, Morley D. Hollenberg

Research output: Contribution to journalArticle

6 Citations (Scopus)

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, PGF , 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 PGF, 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, PGF or KCl. COX-1/2 inhibitors blocked the contractions induced by all the agonists, except KCl and PGF. Conclusion and Implications PAR 1/2-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.

Original languageEnglish
Pages (from-to)2413-2425
Number of pages13
JournalBritish Journal of Pharmacology
Volume171
Issue number9
DOIs
Publication statusPublished - May 2014

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Keywords

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

ASJC Scopus subject areas

  • Pharmacology

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