Ligand-based gene expression profiling reveals novel roles of glucocorticoid receptor in cardiac metabolism.
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.
Yoshikawa
Noritada
N
Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, Univ. of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
Nagasaki
Masao
M
Sano
Motoaki
M
Tokudome
Satori
S
Ueno
Kazuko
K
Shimizu
Noriaki
N
Imoto
Seiya
S
Miyano
Satoru
S
Suematsu
Makoto
M
Fukuda
Keiichi
K
Morimoto
Chikao
C
Tanaka
Hirotoshi
H
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D019556:COS Cells; D002522:Chlorocebus aethiops; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006321:Heart / Q000502:physiology*; D006727:Hormone Antagonists / Q000494:pharmacology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D015735:Mifepristone / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D054467:Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D011281:Pregnatrienes / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
D000893:Anti-Inflammatory Agents; D006727:Hormone Antagonists; C520013:Klf15 protein, rat; D051741:Kruppel-Like Transcription Factors; D008024:Ligands; D011281:Pregnatrienes; D011965:Receptors, Glucocorticoid; D015735:Mifepristone; D051546:Cyclooxygenase 2; D054467:Phospholipases A2; C005924:cortivazol