Hamilton J R, Frauman A G, Cocks T M
Department of Pharmacology, University of Melbourne, Victoria, Australia.
Circ Res. 2001 Jul 6;89(1):92-8. doi: 10.1161/hh1301.092661.
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 micromol/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 micromol/L). Exposure of HCAs to interleukin (IL)-1alpha (1 ng/mL, 12 hours) or tumor necrosis factor-alpha (3 nmol/L, 12 hours) did not affect PAR1 expression but increased PAR2 and PAR4 mRNA levels by approximately 5- and 4-fold, respectively, as determined by quantitative polymerase chain reaction. Similar IL-1alpha treatment did not affect TFLLR-induced relaxations but revealed significant endothelium-dependent relaxations to SLIGKV (100 micromol/L, 61.4+/-6.7%) and GYPGQV (100 micromol/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.
蛋白酶激活受体（PAR）1和PAR2在血管内皮细胞上表达，并介导多种物种的内皮依赖性舒张，PAR4激动剂在大鼠主动脉中引起类似反应。迄今为止，尽管在这些组织中PAR1和PAR2均在内皮细胞中表达，但仅有PAR1被报道介导人类动脉的舒张。由于炎症刺激会增加培养的人内皮细胞中PAR2的表达，本研究调查了类似刺激对人离体冠状动脉（HCA）中PARs的影响。在用于等长张力测量的HCA环段中，选择性PAR1激活肽TFLLR（0.01至10 μmol/L）引起预收缩制剂的内皮依赖性舒张。PAR2激活肽SLIGKV和PAR4激活肽GYPGQV（分别高达100 μmol/L）对血管张力几乎没有影响或没有引起变化。将HCA暴露于白细胞介素（IL）-1α（1 ng/mL，12小时）或肿瘤坏死因子-α（3 nmol/L，12小时）不影响PAR1的表达，但通过定量聚合酶链反应测定，PAR2和PAR4的mRNA水平分别增加了约5倍和4倍。类似的IL-1α处理不影响TFLLR诱导的舒张，但显示出对SLIGKV（100 μmol/L，61.4±6.7%）和GYPGQV（100 μmol/L，34.8±6.4%）有显著的内皮依赖性舒张。这些研究首次证明了原位人动脉中功能性PAR2和PAR4的存在。PAR2和PAR4表达的选择性上调以及暴露于炎症刺激后HCA中血管反应的增加表明这些内皮受体在炎症过程中发挥作用。
