P38 MAPK mediates COX-2 gene expression by corticosterone in cardiomyocytes.
P38 MAPK mediates COX-2 gene expression by corticosterone in cardiomyocytes.
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DOI：
10.1016/j.cellsig.2008.07.003
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发表时间：
2008-11
影响因子：
4.8
通讯作者：
Haipeng Sun;Beibei Xu;H. Inoue;Qin M. Chen
中科院分区：
文献类型：
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作者：
Haipeng Sun;Beibei Xu;H. Inoue;Qin M. Chen
本实验室最近的研究发现，皮质类固醇可诱导心肌细胞环氧合酶-2（考克斯-2）基因的转录激活。在这里，我们报告，考克斯-2基因启动子突变的研究表明，在皮质酮诱导的考克斯-2基因表达的cAMP反应元件结合蛋白（CREB）的作用。皮质酮引起心肌细胞中p38 MAPK的活化和随后CREB在丝氨酸133处的磷酸化。p38 MAPK抑制剂SB 202190和SB 203580可阻断皮质酮诱导CREB磷酸化和考克斯-2基因表达，而显性失活的p38 MAPK或CREB可阻断皮质酮激活考克斯-2启动子。皮质酮不诱导心脏成纤维细胞或糖皮质激素受体转染的HEK293细胞中p38 MAPK激活或COX 2表达，表明p38 MAPK激活是细胞特异性的，并且是皮质酮诱导心肌细胞中考克斯-2表达所必需的。糖皮质激素受体拮抗剂米非司酮抑制皮质酮诱导的考克斯-2基因表达，但不能抑制p38 MAPK激活或CREB磷酸化。相反，抑制p38 MAPK并不能阻止皮质酮激活糖皮质激素受体。结果提示，心肌细胞中考克斯-2基因的表达受糖皮质激素受体和p38 MAPK两条平行的信号通路共同调控。
Recent work from our laboratory found that corticosteroids induce transcriptional activation of cyclooxygenase-2 (COX-2) gene in cardiomyocytes. Here we report that COX-2 gene promoter mutation studies indicate a role of cAMP response element-binding protein (CREB) in corticosterone-induced COX-2 gene expression. Corticosterone causes activation of p38 MAPK and subsequent CREB phosphorylation at serine 133 in cardiomyocytes. The inhibitors of p38 MAPK, SB202190 and SB203580, block corticosterone from inducing CREB phosphorylation and COX-2 gene expression while dominant-negative p38 MAPK or CREB prevents corticosterone from activating COX-2 promoter. Corticosterone does not induce p38 MAPK activation or COX2 expression in cardiac fibroblasts or HEK293 cells transfected with glucocorticoid receptor, suggesting that p38 MAPK activation is cell specific and necessary for corticosterone-induced COX-2 expression in cardiomyocytes. While glucocorticoid receptor antagonist mifepristone inhibits COX-2 gene induction by corticosterone, mifepristone fails to inhibit p38 MAPK activation or CREB phosphorylation. In contrast, inhibition of p38 MAPK does not prevent corticosterone from activating glucocorticoid receptor. Our data suggest that two parallel signaling pathways, glucocorticoid receptor and p38 MAPK, act in concert to regulate the expression of COX-2 gene in cardiomyocytes.