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This Article Full Text Full Text (PDF) Supplemental Tables All Versions of this Article: 296/6/E1363    most recent 90767.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Yoshikawa, N. Articles by Tanaka, H. PubMed PubMed Citation Articles by Yoshikawa, N. Articles by Tanaka, H.

Ligand-based gene expression profiling reveals novel roles of glucocorticoid receptor in cardiac metabolism

¹Division of Clinical Immunology, Advanced Clinical Research Center, ²Research Hospital, ³Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo; ⁴Department of Regenerative Medicine and Advanced Cardiac Therapeutics, ⁵Department of Biochemistry and Integrative Medical Biology, Keio University School of Medicine, Tokyo; and ⁶Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Saitama, Japan

Submitted 16 September 2008 ; accepted in final form 13 March 2009

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.

endocrinology; cardiovascular system; KLF15; cylooxygenase-2; phospholipase A2