title: Ligand-based gene expression profiling reveals novel roles of glucocorticoid receptor in cardiac metabolism.
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.
authors.affiliation: 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.
authors.forename: Noritada
authors.initials: N
authors.lastname: Yoshikawa
authors.forename: Masao
authors.initials: M
authors.lastname: Nagasaki
authors.forename: Motoaki
authors.initials: M
authors.lastname: Sano
authors.forename: Satori
authors.initials: S
authors.lastname: Tokudome
authors.forename: Kazuko
authors.initials: K
authors.lastname: Ueno
authors.forename: Noriaki
authors.initials: N
authors.lastname: Shimizu
authors.forename: Seiya
authors.initials: S
authors.lastname: Imoto
authors.forename: Satoru
authors.initials: S
authors.lastname: Miyano
authors.forename: Makoto
authors.initials: M
authors.lastname: Suematsu
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
authors.forename: Chikao
authors.initials: C
authors.lastname: Morimoto
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Tanaka
mesh_terms: 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
chemical_list: 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