Association between 5-lipoxygenase expression and plaque instability in humans
Association between 5-lipoxygenase expression and plaque instability in humans
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DOI：
10.1161/01.atv.0000172632.96987.2d
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发表时间：
2005-08-01
影响因子：
8.7
通讯作者：
Stafforini, DM
中科院分区：
文献类型：
--
作者：
Cipollone, F;Mezzetti, A;Stafforini, DM
目的：最近的研究表明5-脂氧合酶（5-LO）参与动脉粥样硬化的发展。然而，5-LO作为动脉粥样硬化斑块不稳定性的调节剂的作用先前在人类中尚未报道。因此，本研究的目的是分析5-LO在人颈动脉斑块的表达，并探讨这种酶可能导致斑块不稳定和rupture.Methods和结果的机制-我们获得了60例接受颈动脉内膜切除术的动脉粥样硬化斑块。我们根据斑块不稳定性的临床证据将斑块分为症状性和症状性。斑块不稳定的临床证据通过评估狭窄引起的近期缺血症状和通过计算机断层扫描确定的同侧脑病变的存在来提供。通过免疫组织化学、免疫印迹和光密度分析，分析斑块中的CD68+巨噬细胞、CD3 + T细胞、α-肌动蛋白+平滑肌细胞、5-LO、环氧合酶2、基质金属蛋白酶（MMP）-2和MMP-9。酶谱法测定MMP活性。分别通过ELISA和天狼星红偏振定量白三烯（LT）B-4和胶原。与无症状患者相比，有症状患者的巨噬细胞富集区和T细胞富集区的百分比更大（25 +/-6% vs. 8 +/-4%，P <0.0001，74 +/-17 vs. 18 +/-4cell/mm（2），P <0.003）. 5-有症状斑块中LO表达高于无症状斑块（24 +/-4%对6 +/-3%，P <0.0001），并与MMP-2和MMP-9表达增加相关（27 +/-4%对7 +/-3%，P <0.0001，29 +/-5%对8 +/-2%，P <0.0001）和活性，胶原蛋白含量降低（6.9 +/-2.4%对17.8 +/-3.1%，P <0.01）。免疫荧光显示5-LO和MMPs共定位于活化的巨噬细胞。值得注意的是，有症状斑块中较高的5-LO与LTB4产生增加相关（18.15 +/-3.56对11.27 +/-3.04 ng/g组织，P <0.0001）.结论-与无症状斑块相比，5-LO的表达在有症状斑块中升高，并与急性缺血综合征相关，可能通过产生LTB4，随后MMP生物合成和斑块破裂。
Objective - The participation of 5- lipoxygenase ( 5- LO) in the development of atherosclerosis has been suggested by recent studies. However, a role for 5- LO as a modulator of atherosclerotic plaque instability has not been previously reported in humans. Thus, the aims of this study was to analyze the expression of 5- LO in human carotid plaques and to investigate the mechanism by which this enzyme could lead to plaque instability and rupture.Methods and Results - We obtained atherosclerotic plaques from 60 patients undergoing carotid endarterectomy. We divided the plaques into symptomatic and symptomatic according to clinical evidence of plaque instability. Clinical evidence of plaque instability was provided by the assessment of recent ischemic symptoms attributable to the stenosis and by the presence of ipsilateral cerebral lesion( s) determined by computed tomography. Plaques were analyzed for CD68 + macrophages, CD3 + T cells, alpha- actin + smooth muscle cells, 5- LO, cyclooxygenase 2, matrix metalloproteinase ( MMP)- 2, and MMP- 9 by immunohistochemical, immunoblotting, and densitometric analyses. MMP activity was assessed by zymography. Leukotriene ( LT) B-4 and collagen were quantified by ELISA and Sirius red polarization, respectively. The percentage of macrophage- rich and T- cell - rich areas was larger in symptomatic compared with asymptomatic patients ( 25 +/- 6% versus 8 +/- 4%, P < 0.0001, and 74 +/- 17 versus 18 +/- 4 cell/ mm(2), P < 0.003). 5- LO expression was higher in symptomatic compared with asymptomatic plaques ( 24 +/- 4% versus 6 +/- 3%, P < 0.0001) and was associated with increased MMP- 2 and MMP- 9 expression ( 27 +/- 4% versus 7 +/- 3%, P < 0.0001, and 29 +/- 5% versus 8 +/- 2%, P < 0.0001) and activity and with decreased collagen content ( 6.9 +/- 2.4% versus 17.8 +/- 3.1%, P < 0.01). Immunofluorescence showed that 5- LO and MMPs colocalize in activated macrophages. Notably, higher 5- LO in symptomatic plaques correlated with increased LTB4 production ( 18.15 +/- 3.56 versus 11.27 +/- 3.04 ng/ g tissue, P < 0.0001).Conclusions - The expression of 5- LO is elevated in symptomatic compared with asymptomatic plaques and is associated with acute ischemic syndromes, possibly through the generation of LTB4, subsequent MMP biosynthesis, and plaque rupture.