cAMP modulates glucocorticoid-induced protein accumulation and glucocorticoid receptor in cardiomyocytes.
Glucocorticoids have complex effects on cardiac muscle growth in vivo, and one possible reason may the regulatory cross talk between glucocorticoids and second messengers. In this study we investigated the effect of adenosine 3',5'-cyclic monophosphate (cAMP), shown to affect cardiomyocyte growth and glucocorticoid action in several systems, on glucocorticoid-induced protein accumulation and glucocorticoid receptor (GR) in neonatal rat cardiomyocytes. Dexamethasone (DEX) decreased the protein-to-DNA ratio, and 8-bromoadenosine 3',5'-cyclic monophosphate (BrcAMP) or forskolin increased this ratio. The inhibitory effect of DEX was potentiated by an elevated cAMP, despite the stimulatory effect of cAMP alone. Nuclear GR binding was increased by BrcAMP, with no change in GR mRNA or protein levels, via increased affinity of nuclear GR. H-89 blocked the effects of BrcAMP. In conclusion, glucocorticoids have an inhibitory effect on protein accumulation in cardiomyocytes via GR, an effect potentiated by elevated cAMP via increased nuclear GR binding. These results suggest that glucocorticoid effects on cardiomyocytes may be modulated by cAMP-mediated mechanisms, which may produce the complex effects of glucocorticoids on cardiomyocyte growth in vivo.
Sato
A
A
Baker Medical Research Institute, Prahran, Victoria, Australia.
Sheppard
K E
KE
Fullerton
M J
MJ
Funder
J W
JW
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003001:Cloning, Molecular; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D003907:Dexamethasone / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000096:biosynthesis; D013449:Sulfonamides; D014158:Transcription, Genetic / Q000187:drug effects
D004791:Enzyme Inhibitors; D007546:Isoquinolines; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D011994:Recombinant Proteins; D013449:Sulfonamides; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D003907:Dexamethasone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide