Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions
Augmented expression of cyclooxygenase-2 in human atherosclerotic lesions
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DOI：
10.1016/s0002-9440(10)65230-3
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发表时间：
1999-10-01
影响因子：
6
通讯作者：
Libby, P
中科院分区：
文献类型：
--
作者：
Schönbeck, U;Sukhova, GK;Libby, P
环氧合酶-1（考克斯-1）和考克斯-2将花生四烯酸转化为前列腺素H-2，前列腺素H-2是其他类花生四烯酸和血栓烷的前体，在血管病理生理学中是重要的类花生酸。本研究验证了以下假设：人动脉粥样硬化和非动脉粥样硬化动脉表达两种不同的考克斯亚型，考克斯-1 mRNA和蛋白定位于正常动脉的内皮和中膜平滑肌细胞（n = 5），而考克斯-2表达未检测到。相比之下，动脉粥样硬化（n = 7）病变包含考克斯-1和考克斯-2，共定位主要与巨噬细胞的肩部区域和脂质核心周边，而平滑肌细胞显示较低的水平，如免疫组化和原位杂交分析所示。此外，斑块中的微血管内皮显示出明显的两种亚型的染色。与免疫组织化学研究雅阁的是，来自正常动脉的蛋白提取物的Western印迹分析揭示了组成型考克斯-1，而不是考克斯-2的表达。然而，动脉粥样硬化病变的提取物含有考克斯-1和考克斯-2蛋白，检测为两种约70和50 kd的免疫反应性蛋白。在体外培养几天后，巨噬细胞组成型表达短形式的考克斯-1/-2，而不是70-kd蛋白。这些结果揭示了在人类动脉粥样硬化中起作用的炎症途径。特别是，考虑到选择性考克斯-2抑制剂的出现，考克斯-2在动脉粥样硬化中的表达而不是在未受影响的动脉中的表达具有治疗意义。
Cyclooxygenase-1 (Cox-1) and Cox-2 convert arachidonic acid to prostaglandin H-2, the precursor of other prostaglandins and thromboxanes, eicosanoids important in vascular pathophysiology, However, knowledge of the expression of cyclooxygenases within atherosclerotic lesions is scant. This study tested the hypothesis that human atheroma and nonatherosclerotic arteries express the two Cox isoforms differentially, Cox-1 mRNA and protein localized on endothelial and medial smooth muscle cells of normal arteries (n = 5), whereas Cox-2 expression was not detectable. In contrast, atheromatous (n = 7) lesions contained both Cox-1 and Cox-2, colocalizing mainly with macrophages of the shoulder region and Lipid core periphery, whereas smooth muscle cells showed lower levels, as demonstrated by immunohistochemical and ill situ hybridization analysis. Furthermore, microvascular endothelium in plaques showed notable staining for both isoforms, In accord with immunohistochemical studies, Western blot analysis of protein extracts from normal arteries revealed constitutive Cox-1, but not Cox-2, expression. Extracts of atheromatous lesions, however, contained both Cox-1 and Cox-2 protein, detected as two immunoreactive proteins of approximately 70 and 50 kd. Macrophages expressed the short form of Cox-1/-2 constitutively after several days of in vitro culture, rather than the 70-kd protein. These results shed new light on the inflammatory pathways that operate in human atheroma. In particular, the expression of Cox-2 in atheromatous, but not in unaffected, arteries has therapeutic implications, given the advent of selective Cox-2 inhibitors.