Association between prostaglandin E receptor subtype EP4 overexpression and unstable phenotype in atherosclerotic plaques in human
Association between prostaglandin E receptor subtype EP4 overexpression and unstable phenotype in atherosclerotic plaques in human
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DOI：
10.1161/01.atv.0000177814.41505.41
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发表时间：
2005-09-01
影响因子：
8.7
通讯作者：
Mezzetti, A
中科院分区：
文献类型：
--
作者：
Cipollone, F;Fazia, ML;Mezzetti, A
目的：我们最近证实，诱导型环氧合酶/前列腺素E合成酶-1(COX-2/mPGES-1)在症状性斑块中过表达，与PGE(2)依赖的金属蛋白酶(MMPs)的生物合成和斑块破裂有关。然而，目前尚不清楚4种PGE(2)受体中的哪一种(EP1-4)介导了巨噬细胞金属蛋白酶的产生。本研究旨在研究有症状和无症状颈动脉内膜切除术患者颈动脉内膜切除术后斑块中EP1-4的表达特征及其与炎症浸润程度、环氧合酶-2/mPGES-1和基质金属蛋白酶的表达以及患者临床特征的关系。方法与结果：采用免疫组织化学、逆转录聚合酶链式反应和免疫印迹法检测斑块中环氧合酶-2、环氧合酶-1、EP1-4、基质金属蛋白酶-2和基质金属蛋白酶-9的表达，酶谱法检测基质金属蛋白酶活性。我们观察到EP4免疫反应强，仅EP2表达很弱，在动脉粥样硬化斑块中不表达EP1和EP3。EP4在富含基质金属蛋白酶的症状性病变中更为丰富，而EP2在症状性斑块和无症状性斑块中的表达差异无统计学意义。EP4拮抗剂L-161 982可抑制前列腺素E_2诱导的基质金属蛋白酶的形成，而其失活类似物L-161 983和EP2拮抗剂AH6809则不能抑制其抑制作用。结论：EP4过度表达与动脉粥样硬化斑块炎症反应增强有关。这种作用可能通过诱导罪魁祸首金属蛋白酶的表达而导致斑块的不稳定。
Objective - We recently demonstrated that inducible cyclooxygenase/PGE synthase-1 (COX-2/mPGES-1) are overexpressed in symptomatic plaques in association with PGE(2)-dependent metalloproteinase ( matrix metalloproteinase [MMP]) biosynthesis and plaque rupture. However, it is not known which of the 4 PGE(2) receptors (EP1 - 4) mediates macrophage metalloproteinase generation. The aim of this study was to characterize EP1 - 4 expression in plaques from symptomatic and asymptomatic patients undergoing carotid endarterectomy and correlate it with the extent of inflammatory infiltration, COX-2/mPGES-1 and MMP expression and clinical features of patients' presentation.Methods and Results - Plaques were analyzed for COX-2, mPGES-1, EP1 - 4, MMP-2, and MMP-9 by immunohistochemistry, reverse-transcription polymerase chain reaction and Western blot; zymography was used to detect MMP activity. We observed strong EP4 immunoreactivity, only very weak staining for EP2, and no expression of EP1 and EP3 in atherosclerotic plaques. EP4 was more abundant in MMP-rich symptomatic lesions, whereas EP2 was no different between symptomatic and asymptomatic plaques. Finally, MMP induction by PGE2 in vitro was inhibited by the EP4 antagonist L-161 982, but not by its inactive analog L-161 983 or by the EP2 antagonist AH6809.Conclusions - This study shows that EP4 overexpression is associated with enhanced inflammatory reaction in atherosclerotic plaques. This effect might contribute to plaque destabilization by inducing culprit metalloproteinase expression.