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

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 mol/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 mol/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 Ϸ5-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 mol/L, 61.4Ϯ6.7%) and GYPGQV (100 mol/L, 34.8Ϯ6.4%). 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.

Proteinase-activated receptor 2 is involved in the behavioural changes associated with sickness behaviour

“…Our data indicates that PAR2 mRNA expression remains unaltered following LPS injection both acutely and after 24 hrs thus suggesting that changes in PAR2 expression do not account for the changes in sickness behaviour observed in PAR2 -/-mice. Our findings are in contrast to a number of studies that have shown that LPS as well as IL-1β and TNFα can lead to increased PAR2 expression in a variety of preparations (Hamilton et al, 2001;Morello et al, 2005;Ritchie et al, 2007). Thus our data implies that activation of PAR2 per se accounts for the role of PAR2 in sickness behaviour but the exact identity of the PAR2 activator(s) remains to be determined with several potential candidates and mechanisms by which this may occur outlined above.…”

Factor VII activating protease (FSAP) regulates the expression of inflammatory genes in vascular smooth muscle and endothelial cells

“…Activation of PAR1 or PAR2 in mice caused a decrease in blood pressure which was abolished in PAR1 -/-and PAR2 -/-mice respectively 90,129,130 .…”

“…PAR2 is highly expressed in prostate, small intestine, colon, heart, liver, kidney, pancreas and arteries. In addition PAR2 is expressed in various cancer cell lines 89,90 , EC and VSMC…”

“…PAR3 is expressed in heart, liver, kidney, pancreas, thymus, small intestine, colon, stomach, lymphatic node, trachea and bone marrow 36 , EC 92 but not in VSMC 91 . PAR4 is expressed in most tissues besides heart, brain, spinal cord, and peripheral blood leukocytes 93 and is expressed in human coronary artery 90 . PARs are activated by a variety of proteases and have an important role in many pathophysiological processes.…”

Proteinase-Activated Receptor-2 Induction by Neuroinflammation Prevents Neuronal Death during HIV Infection

“…Although not as extensively studied as PAR-1, PAR-2 has also been shown to be involved in the pathogenesis of systemic inflammatory disorders (25)(26)(27)(28)(29). Nonetheless, PAR-2 is expressed on hippocampal, cortical, thalamic, hypothalamic, and striatal neurons in the brain and on dorsal root ganglia, myenteric, and submucosal neurons in the peripheral nervous system (7-9, 30, 31).…”