RRC ID 19613
Author Yoshikawa N, Nagasaki M, Sano M, Tokudome S, Ueno K, Shimizu N, Imoto S, Miyano S, Suematsu M, Fukuda K, Morimoto C, Tanaka H.
Title Ligand-based gene expression profiling reveals novel roles of glucocorticoid receptor in cardiac metabolism.
Journal Am. J. Physiol. Endocrinol. Metab.
Abstract Recent studies have documented various roles of adrenal corticosteroid signaling in cardiac physiology and pathophysiology. It is known that glucocorticoids and aldosterone are able to bind glucocorticoid receptor (GR) and mineralocorticoid receptor, and these ligand-receptor interactions are redundant. It, therefore, has been impossible to delineate how these nuclear receptors couple with corticosteroid ligands and differentially regulate gene expression for operation of their distinct functions in the heart. Here, to particularly define the role of GR in cardiac muscle cells, we applied a ligand-based approach involving the GR-specific agonist cortivazol (CVZ) and the GR antagonist RU-486 and performed microarray analysis using rat neonatal cardiomyocytes. We indicated that glucocorticoids appear to be a major determinant of GR-mediated gene expression when compared with aldosterone. Moreover, expression profiles of these genes highlighted numerous roles of glucocorticoids in various aspects of cardiac physiology. At first, we identified that glucocorticoids, via GR, induce mRNA and protein expression of a transcription factor Kruppel-like factor 15 and its downstream target genes, including branched-chain aminotransferase 2, a key enzyme for amino acid catabolism in the muscle. CVZ treatment or overexpression of KLF15 decreased cellular branched-chain amino acid concentrations and introduction of small-interfering RNA against KLF15 cancelled these CVZ actions in cardiomyocytes. Second, glucocorticoid-GR signaling promoted gene expression of the enzymes involved in the prostaglandin biosynthesis, including cyclooxygenase-2 and phospholipase A2 in cardiomyocytes. Together, we may conclude that GR signaling should have distinct roles for maintenance of cardiac function, for example, in amino acid catabolism and prostaglandin biosynthesis in the heart.
Volume 296(6)
Pages E1363-73
Published 2009-6
DOI 10.1152/ajpendo.90767.2008
PII 90767.2008
PMID 19293335
MeSH Animals Anti-Inflammatory Agents / pharmacology COS Cells Cercopithecus aethiops Cyclooxygenase 2 / genetics Cyclooxygenase 2 / metabolism Gene Expression Profiling* Gene Expression Regulation / drug effects Gene Expression Regulation / physiology Heart / physiology* Hormone Antagonists / pharmacology Kruppel-Like Transcription Factors / genetics Kruppel-Like Transcription Factors / metabolism Ligands Mifepristone / pharmacology Myocardium / cytology Myocardium / metabolism* Myocytes, Cardiac / cytology Myocytes, Cardiac / physiology Oligonucleotide Array Sequence Analysis Phospholipases A2 / genetics Phospholipases A2 / metabolism Pregnatrienes / pharmacology Protein Binding / physiology Rats Receptors, Glucocorticoid / genetics* Receptors, Glucocorticoid / metabolism* Transfection
IF 4.125
Times Cited 19
Human and Animal Cells COS-7 (RCB0539)