TY - JOUR
T1 - Inhibitors of GSK-3 prevent corticosterone from inducing COX-1 expression in cardiomyocytes
AU - Sun, Haipeng
AU - Chen, Qin M.
N1 - Funding Information:
Acknowledgments Work from our laboratory has been supported by NIH R01 ES10826, R01 HL 076530, Arizona Disease Control Research Commission, and the American Heart Association. We thank Ms. Yan Lin for technical assistance. MMTV-Luciferase construct was generous gift from Dr. Roger Miesfeld.
PY - 2008/6
Y1 - 2008/6
N2 - 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-3β increased COX-1 promoter activity, which was abolished by LiCl. LiCl increased inhibitory GSK-3α/β phosphorylation at Ser21/Ser9, while BIO or SB216763 prevented stimulatory phosphorylation at Tyr279/Tyr216 of GSK-3α/β. 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.
AB - 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-3β increased COX-1 promoter activity, which was abolished by LiCl. LiCl increased inhibitory GSK-3α/β phosphorylation at Ser21/Ser9, while BIO or SB216763 prevented stimulatory phosphorylation at Tyr279/Tyr216 of GSK-3α/β. 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.
KW - Corticosteroids
KW - Cyclooxygenase
KW - Glycogen synthase kinases
KW - Pharmacological inhibitors
KW - Transcription
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U2 - 10.1007/s12012-008-9018-y
DO - 10.1007/s12012-008-9018-y
M3 - Article
C2 - 18584335
AN - SCOPUS:51449088620
SN - 1530-7905
VL - 8
SP - 93
EP - 100
JO - Cardiovascular Toxicology
JF - Cardiovascular Toxicology
IS - 2
ER -