Proteinase‐activated receptors, PAR1 & PAR2, regulate porcine coronary contractility via tyrosine kinase‐MAPKinase signaling involving a cyclooxygenase (COX)‐1 product

Abstract

ObjectivePARs 1 and 2 regulate vascular tension and also trigger both tyrosine kinase (PYK) and MAPKinase signals, in part via EGF receptor (EGFR) transactivation. We hypothesized that PAR‐triggered MAPK and PYK activities regulate porcine coronary artery (PCA) tension via EGFR activation.MethodsContractions of L‐NAME‐treated PCA rings ± functional endothelium stimulated by PAR1/2‐selective activating peptides (PAR‐APs), EGF, angiotensin‐II (AngII) and PGF2α were monitored in the absence and presence of the signal pathway inhibitors: PP1 (Src kinase), AG1478 (EGFR kinase), U0126 (MAPK), PD98059 (MAPK), and the COX inhibitors, indomethacin (INDO, COX1,2), SC560 (COX1), & NS398 (COX2).ResultsEndothelium‐independent contractions by PAR1/2‐APs, Ang‐II, and EGF (but not by PGF2α) were inhibited by PP1, U0126, & PD98059. AG1478 blocked mainly PAR2‐AP and EGF contractions, Further, PAR‐AP & Ang‐II contractions, blocked by INDO & SC560, were mimicked by arachidonate. In contrast, PGF2α‐induced contraction was not affected by any inhibitor used.ConclusionsPARs 1 & 2, like AngII, regulate coronary tension via a PYK‐MAPK pathway involving a COX1 metabolite, but by distinct GPCR mechanisms that differentially transactivate the EGFR. Support: CIHR‐Canada, Qatar Foundation NPPR and the Heart & Stroke Foundation of Canada.