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.

Essential role of stress hormone signaling in cardiomyocytes for the prevention of heart disease

“…Whether the Dmd and RyR2 genes are primary or secondary targets of GR regulation is currently unknown. However, Klf15, Ptgds, and MuRF1 are bona fide glucocorticoid-responsive target genes that are induced by activated GR (11)(12)(13)(14). Accordingly, in the absence of an intact GR signaling pathway in cardiomyocytes, the expression of these genes is significantly repressed.…”

Endogenous Prostaglandin D 2 and Its Metabolites Protect the Heart Against Ischemia–Reperfusion Injury by Activating Nrf2

“…For example, glucocorticoids suppress COX-2 expression in immune cells, whereas they increase COX-2 expression in cardiomyocytes. 6,14,15 The induction of COX-2 is cardioprotective in the context of I/R injury and post-myocardial infarction cardiac remodeling. However, the treatment of acute myocardial infarction with glucocorticoids has yielded inconsistent and conflicting results.…”

Glucocorticoid protects rodent hearts from ischemia/reperfusion injury by activating lipocalin-type prostaglandin D synthase–derived PGD2 biosynthesis

“…15,16), or ALD (17). Unexpectedly, we found that the expression of genes that encode 2 key enzymes in a common pathway of prostaglandin biosynthesis were upregulated by glucocorticoids via the GR in cardiomyocytes: phospholipase A2 group IVA (Pla2g4a; encoding cytosolic calcium-dependent phospholipase A2 [cPLA2]), which belongs to the class of cPLA2s that preferentially cleave arachidonic acid from membrane phospholipids; and pros-…”