title: LY294002 inhibits glucocorticoid-induced COX-2 gene expression in cardiomyocytes through a phosphatidylinositol 3 kinase-independent mechanism.
abstract: 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 CT-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. Tetraethylammonium (TEA), a potassium channel blocker, and nimodipine, a calcium channel blocker, both attenuated CT from inducing COX-2 gene expression. CT was found to increase intracellular Ca(2+) 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.
authors.affiliation: Interdisciplinary Graduate Program of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Haipeng
authors.initials: H
authors.lastname: Sun
authors.forename: Beibei
authors.initials: B
authors.lastname: Xu
authors.forename: Elena
authors.initials: E
authors.lastname: Sheveleva
authors.forename: Qin M
authors.initials: QM
authors.lastname: Chen
mesh_terms: D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005938:Glucocorticoids / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D009553:Nimodipine / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019789:Tetraethylammonium / Q000494:pharmacology; D013997:Time Factors; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D002118:Calcium; D002121:Calcium Channel Blockers; D002867:Chromones; D051546:Cyclooxygenase 2; D005938:Glucocorticoids; D009025:Morpholines; D009553:Nimodipine; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010879:Piperazines; D026902:Potassium Channel Blockers; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011965:Receptors, Glucocorticoid; D019789:Tetraethylammonium; D000077191:Wortmannin; C093555:LY 303511; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C489691:Ptgs2 protein, rat