Circulation Research. 2001;89:92-98
Published online before print June 21, 2001, doi: 10.1161/hh1301.092661
Published online before print June 21, 2001, doi: 10.1161/hh1301.092661
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© 2001 American Heart Association, Inc.
Clinical Research |
Increased Expression of Protease-Activated Receptor-2 (PAR2) and PAR4 in Human Coronary Artery by Inflammatory Stimuli Unveils Endothelium-Dependent Relaxations to PAR2 and PAR4 Agonists
From the Department of Pharmacology (J.R.H., T.M.C.), University of Melbourne, Victoria, Australia, and the Clinical Pharmacology and Therapeutics Unit (A.G.F.), Department of Medicine, Austin and Repatriation Medical Centre, Heidelberg, Victoria, Australia.
Correspondence to Tom Cocks, PhD, Department of Pharmacology, University of Melbourne, Victoria 3010, Australia. E-mail thomasmc{at}unimelb.edu.au
Abstract
Abstract—Protease-activated
receptor (PAR)1 and PAR2 are expressed on vascular
endothelial cells and mediate
endothelium-dependent relaxation in several species,
and PAR4 agonists cause similar responses in rat aortas. To date, only
PAR1 has been reported to mediate relaxation of human arteries despite
endothelial cell expression of both PAR1 and PAR2 in
these tissues. Because inflammatory stimuli increase PAR2 expression in
human endothelial cells in culture, the present
study investigated the effect of similar stimuli on PARs in human
isolated coronary arteries (HCAs). In HCA ring segments
suspended for isometric tension measurements, the selective
PAR1-activating peptide, TFLLR (0.01 to 10 µmol/L), caused
endothelium-dependent relaxation of precontracted
preparations. Little or no change in vascular tension was elicited by
either the PAR2- or PAR4-activating peptides, SLIGKV and GYPGQV,
respectively (up to 100 µmol/L). Exposure of HCAs to interleukin
(IL)-1
(1 ng/mL, 12 hours) or tumor necrosis factor- (3 nmol/L,
12 hours) did not affect PAR1 expression but increased PAR2 and
PAR4 mRNA levels by 
5- and 4-fold, respectively, as determined by
quantitative polymerase chain reaction. Similar IL-1 treatment did
not affect TFLLR-induced relaxations but revealed significant
endothelium-dependent relaxations to SLIGKV (100
µmol/L, 61.4±6.7%) and GYPGQV (100 µmol/L, 34.8±6.4%). These
studies are the first to demonstrate functional PAR2 and PAR4 in human
arteries in situ. The selective upregulation of PAR2 and PAR4
expression and the increased vascular response in HCAs after exposure
to inflammatory stimuli suggest a role for these
endothelial receptors during inflammation.
Key Words: endothelium • human coronary arteries • protease-activated receptors
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