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

Noritada Yoshikawa, Masao Nagasaki, Motoaki Sano, Satori Tokudome, Kazuko Ueno, Noriaki Shimizu, Seiya Imoto, Satoru Miyano, Makoto Suematsu, Keiichi Fukuda, Chikao Morimoto, Hirotoshi Tanaka

研究成果: Article査読

29 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)E1363-E1373
ジャーナルAmerican Journal of Physiology - Endocrinology and Metabolism
296
6
DOI
出版ステータスPublished - 2009 6

ASJC Scopus subject areas

  • 内分泌学、糖尿病および代謝内科学
  • 生理学
  • 生理学(医学)

フィンガープリント

「Ligand-based gene expression profiling reveals novel roles of glucocorticoid receptor in cardiac metabolism」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル