LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism

被引:15
|
作者
Sun, Haipeng [2 ]
Xu, Beibei [1 ]
Sheveleva, Elena [1 ]
Chen, Qin M. [1 ]
机构
[1] Univ Arizona, Dept Pharmacol, Tucson, AZ 85724 USA
[2] Univ Arizona, Interdisciplinary Grad Program Pharmacol & Toxico, Tucson, AZ 85724 USA
关键词
Phosphatidylinositol; 3 kinase inhibitors; Calcium; Cyclooxygenase;
D O I
10.1016/j.taap.2008.05.024
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
glucocorticoids induce COX-2 expression in rat cardiomyocytes. While investigating whether phosphatidylinositol 3 kinase (PI3K) plays a role in corticosterone (CT)-induced COX-2, we found that LY294002 (LY29) but not wortmannin (WM) attenuates CT from inducing COX-2 gene expression. Expression of a dominant-negative mutant of p85 subunit of PI3K failed to inhibit CT from inducing COX-2 expression. CT did not activate PI3K/AKT signaling pathway whereas LY29 and WM decreased the activity of PI3K. LY303511 (LY30), a Structural analogue and a negative control for PI3K inhibitory activity of LY29, also Suppressed COX-2 induction. These data Suggest PI3K-independent mechanisms in regulating CF-induced COX-2 expression. LY29 and LY30 do not inhibit glucocorticoid receptor transactivity. Both compounds have been reported to inhibit Casein Kinase 2 activity and Modulate potassium and calcium levels independent of PI3K, while LY29 has been reported to inhibit mammalian Target of Rapamycin (mTOR), and DNA-dependent Protein Kinase (DNA-PK). Inhibitor of Casein Kinase 2 (CK2), mTOR or DNA-PK failed to prevent CT from inducing COX-2 expression. Tetraethylaammonium (TEA), a potassium channel blocker, and nimodipine, a clacium channel blocker, both attenuated CT from inducing COX-2 gene expression. CT was found to increase intracellular Ca2+ concentration, which can be inhibited by LY29, TEA or nimodipine. These data suggest a possible role of calcium instead of PI3K in CT-induced COX-2 expression in cardiomyocytes. (C) 2008 Elsevier Inc. All rights reserved.
引用
收藏
页码:25 / 32
页数:8
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