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Am J Physiol Cell Physiol 295: C915-C922, 2008. First published July 23, 2008; doi:10.1152/ajpcell.90646.2007
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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Corticosteroids induce COX-2 expression in cardiomyocytes: role of glucocorticoid receptor and C/EBP-β

Haipeng Sun,1 Elena Sheveleva,2 Beibei Xu,2 Hiroyasu Inoue,3 Tim G. Bowden,4 and Qin M. Chen2

1Interdisciplinary Graduate Program of Pharmacology and Toxicology, 4Arizona Cancer Center, and 2Department of Pharmacology, University of Arizona, Tucson, Arizona; and 3National Cardiovascular Center Research Institute, Suita, Osaka, Japan

Submitted 21 December 2007 ; accepted in final form 7 July 2008

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.

gene expression; cyclooxygenase; transcription; protein-protein interaction



Address for reprint requests and other correspondence: Q. M. Chen, Dept. of Pharmacology, Univ. of Arizona, 1501 N. Campbell Ave., Tucson, AZ 85724 (e-mail: qchen{at}email.arizona.edu)







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