Inhibitors of GSK-3 prevent corticosterone from inducing COX-1 expression in cardiomyocytes.
Our recent study has demonstrated that glucocorticoids (GCs) induce cyclooxygenase-1 (COX-1) gene expression in rat cardiomyocytes. While investigating the mechanism underlying corticosterone (CT) induced COX-1, we found that three structurally and mechanistically distinct GSK-3 inhibitors, LiCl, SB216763, and (2'Z,3'E)-6-Bromoindirubin-3'-oxime (BIO), inhibited COX-1 transcription and protein induction. A genetic approach of expressing wild type GSK-3beta increased COX-1 promoter activity, which was abolished by LiCl. LiCl increased inhibitory GSK-3alpha/beta phosphorylation at Ser21/Ser9, while BIO or SB216763 prevented stimulatory phosphorylation at Tyr279/Tyr216 of GSK-3alpha/beta. GSK inhibitors failed to block nuclear translocation of glucocorticoid receptor (GR) or activation of glucocorticoid response element (GRE) by CT treatment. While Sp3 transcription factor mediates CT induced COX-1 expression, GSK inhibitors did not change the level of Sp3 protein or binding of Sp3 transcription factor to COX-1 promoter. The observed effect of GSK-3 inhibitors appears to be unique to COX-1 since LiCl or BIO does not prevent CT from inducing COX-2 gene. We conclude that GSK-3 inhibitors block CT from inducing COX-1 gene expression via a mechanism beyond GR and Sp3 transcription factor.
Sun
Haipeng
H
Interdisciplinary Graduate Program of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA.
Chen
Qin M
QM
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003345:Corticosterone / Q000378:metabolism*; D051545:Cyclooxygenase 1 / Q000096:biosynthesis* / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D004790:Enzyme Induction; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology; D010091:Oximes / Q000494:pharmacology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D051705:Sp3 Transcription Factor / Q000378:metabolism; D014162:Transfection
C483321:6-bromoindirubin-3'-oxime; D007211:Indoles; D008301:Maleimides; D008565:Membrane Proteins; D010091:Oximes; D047428:Protein Kinase Inhibitors; D011965:Receptors, Glucocorticoid; C417521:SB 216763; C497123:Sp3 protein, rat; D051705:Sp3 Transcription Factor; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; D003345:Corticosterone