Corticosteroids induce COX-2 expression in cardiomyocytes: role of glucocorticoid receptor and C/EBP-beta.
Corticosteroids induce COX-2 expression in cardiomyocytes: role of glucocorticoid receptor and C/EBP-beta.
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皮质类固醇诱导心肌细胞中 COX-2 的表达：糖皮质激素受体和 C/EBP-β 的作用。
DOI：
10.1152/ajpcell.90646.2007
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Chen,QinM
中科院分区：
文献类型：
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作者：
Sun,Haipeng;Sheveleva,Elena;Xu,Beibei;Inoue,Hiroyasu;Bowden,TimG;Chen,QinM
心理压力会增加循环系统中糖皮质激素的水平。我们发现，地塞米松给药在成年小鼠心肌考克斯-2的表达升高。生理剂量（0.01-1 μM）的皮质酮（CT）诱导离体乳鼠心肌细胞考克斯-2基因表达。诱导在4 h首次出现，并在1 μM CT处理下保持至少24 h。这种反应可能是心肌细胞类型特异性的，因为CT不诱导心脏成纤维细胞中的考克斯-2表达，并且已知糖皮质激素抑制淋巴细胞和几种器官中的考克斯-2表达。皮质类固醇，而不是雌激素或孕激素，诱导考克斯-2表达。糖皮质激素受体（GR）拮抗剂米非司酮（MF）可抑制CT诱导考克斯-2基因的表达，提示其对心肌细胞的诱导作用依赖GR。考克斯-2基因启动子缺失和突变研究表明CCAAT/增强子结合蛋白-β（C/EBP-β）在CT诱导的考克斯-2基因表达中起作用。染色质免疫沉淀实验表明，CT可使GR和C/EBP-β与考克斯-2启动子结合，而MF预处理可阻断这种结合。免疫共沉淀实验表明，CT诱导GR与C/EBP-β相互作用。针对C/EBP-β的小干扰RNA抑制CT激活考克斯-2启动子或升高考克斯-2蛋白。我们的数据表明，GR和C/EBP-β之间的相互作用有助于CT在心肌细胞中上调考克斯-2基因的转录。
Psychological stress increases the level of glucocorticoids in the circulating system. We found that dexamethasone administration in adult mice elevates the expression of COX-2 in the myocardium. With isolated neonatal cardiomyocytes, corticosterone (CT) at physiologically relevant doses (0.01–1 μM) induces the expression of COX-2 gene. The induction first appeared at 4 h and remained for at least 24 h with 1 μM CT treatment. This response is likely cardiomyocyte cell type specific since CT did not induce COX-2 expression in cardiac fibroblasts and glucocorticoids are known to suppress the expression of COX-2 in lymphocytes and several organs. Corticosteroids, but not estrogen or progesterone, induce COX-2 expression. The glucocorticoid receptor (GR) antagonist mifepristone (MF) prevented CT from inducing COX-2 gene, suggesting a GR-dependent induction in cardiomyocytes. COX-2 gene promoter deletion and mutation studies indicate a role of CCAAT/enhancer binding protein-β (C/EBP-β) in CT-induced COX-2 gene expression. Chromatin immunoprecipitation assays revealed that CT caused the binding of both GR and C/EBP-β to COX-2 promoter, while MF pretreatment blocked such binding. Coimmunoprecipitation experiments demonstrated that CT treatment induced the interaction of GR with C/EBP-β. Small interfering RNA against C/EBP-β prevented CT from activating COX-2 promoter or elevating COX-2 protein. Our data suggest that the interaction between GR and C/EBP-β contributes to elevated COX-2 gene transcription by CT in cardiomyocytes.