© 1996 American Heart Association, Inc.
Articles |
Evidence for the Presence of a Proteinase-Activated Receptor Distinct From the Thrombin Receptor in Vascular Endothelial Cells
From Cardiovascular Pharmacology (J.J.H., L.G., P.W., M. Chintala, M. Chatterjee, E.S.) and Structure Chemistry (R.Z.), Schering-Plough Research Institute, Kenilworth, NJ.
Correspondence to Dr Joyce J. Hwa, Cardiovascular Pharmacology, Schering-Plough Research Institute, 2015 Galloping Hill Rd, Kenilworth, NJ 07033-0530.
Abstract The thrombin receptor was the first cloned G
protein–coupled receptor reported to be activated by
proteolytic cleavage of its extracellular amino terminus. A second
proteinase-activated receptor (PAR-2) was cloned recently
and expressed in Xenopus laevis oocytes. PAR-2 was
activated by trypsin and by a peptide (SLIGRL) derived from the
new amino terminus. Since PAR-2 mRNA was detected in highly
vascularized organs, we compared the physiological
functions of the thrombin receptor and PAR-2 in vascular
endothelium. Thrombin and trypsin both elicited
endothelium-dependent relaxations in
prostaglandin F2
(PGF2)–contracted strips of porcine
coronary artery. Whereas high doses of both thrombin or trypsin
(10 U/mL) caused homologous desensitization, trypsin caused further
relaxation of thrombin-desensitized tissues. Thrombin and
PAR-2–derived peptides (SFLLRN and SLIGRL) both induced
endothelium-dependent relaxations in
PGF2-contracted porcine coronary
arteries. SFLLRN or SLIGRL (30 µmol/L) also showed
homologous desensitization but not cross desensitization. In the
presence of the NO synthase inhibitor
NG-monomethyl-L-arginine
(1 mmol/L), both SFLLRN- and SLIGRL-induced relaxations were partially
inhibited. SFLLRN elicited weak contraction in coronary
arteries without endothelium, whereas SLIGRL had no
effect. Intravenous injection of SFLLRN (1 mg/kg, bolus)
into anesthetized rats elicited a transient depressor response
followed by pronounced pressor response. In contrast,
intravenous administration of SLIGRL (1 mg/kg, bolus)
produced only a marked depressor response. Consistent with the
in vivo data, SFLLRN contracted the
endothelium-rubbed rat aortic rings and aggregated
human platelets in vitro, whereas SLIGRL had no effect. The
finding that both trypsin and SLIGRL induced
endothelium-dependent relaxations indicates the
presence of PAR-2 on endothelial cells. In addition,
both trypsin and SLIGRL elicited relaxations in thrombin- or
SFLLRN-desensitized tissue, suggesting that PAR-2 is distinct from
thrombin receptor in vascular endothelium. The lack of
PAR-2–mediated platelet aggregation or smooth muscle contraction
suggested it might not share the pathogenic properties associated with
the thrombin receptor in the vasculature.
Key Words: endothelial cells • receptors • thrombin • trypsin • serine proteases • endothelium-derived relaxing factors
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