Cross talk between corticosteroids and alpha-adrenergic signalling augments cardiomyocyte hypertrophy: a possible role for SGK1.

OBJECTIVE: Mineralocorticoids and glucocorticoids have been implicated in the pathogenesis of cardiac diseases; however, both in vivo and in vitro studies indicate that changes in the cellular milieu of either the cardiomyocyte and/or cells of the vasculature is required for corticosteroid signalling to be pathological. The aim of the current study was to directly address whether signalling pathways that are activated during myocyte hypertrophy alter corticosteroid signalling and thus enable these steroids to significantly impact on the hypertrophic response.
METHODS: Neonatal rat ventricular cardiomyocytes were treated with phenylephrine or phorbol ester for 48 h to induce myocyte hypertrophy. Following treatment, the expression of glucocorticoid receptor, mineralocorticoid receptor, and 11beta-hydroxysteroid dehydrogenase were determined by ribonuclease protection assay. In addition, the activity of 11beta-hydroxysteroid dehydrogenase and the ability of glucocorticoid and mineralocorticoid receptors to induce serum- and glucocorticoid-induced kinase 1 (SGK1) gene transcription were assessed. Corticosteroid effects on phenylephrine and phorbol ester-induced hypertrophy were determined by measuring atrial natriuretic peptide (ANP) mRNA expression, protein synthesis, or induction of rDNA transcription.
RESULTS: Incubation of cardiomyocytes with phenylephrine and phorbol ester for 48 h led to a hypertrophic response with an associated 8- to 12-fold increase in ANP mRNA and 2-fold increase in rDNA transcription. Cardiomyocyte hypertrophy led to a significant 2-fold increase in glucocorticoid receptor and mineralocorticoid receptor expression that resulted in enhanced receptor signaling as judged via the ability of corticosterone and aldosterone to induce SGK1 gene transcription. 11beta-Hydroxysteroid dehydrogenase2 was not detected in normal or hypertrophied cardiomyocytes, and 11beta-hydroxysteroid dehydrogenase exclusively demonstrated reductase activity, converting the inactive 11-ketometabolite back to active glucocorticoid. 11beta-Hydroxysteroid dehydrogenase1 expression and reductase activity were increased with phorbol ester-induced hypertrophy but not phenylephrine-induced hypertrophy. In basal cardiomyocytes, either aldosterone or corticosterone induced only a minor increase in ANP mRNA and protein synthesis; however, in cardiomyocytes primed with phenylephrine, both corticosteroids significantly potentiated phenylephrine-mediated effects via activation of the glucocorticoid receptor.
CONCLUSION: In the present study we demonstrate that significant cross talk exists in the cardiomyocyte between corticosteroid receptor-activated pathways and both protein kinase C and alpha-adrenergic signalling. Cellular changes associated with the hypertrophic response promote corticosteroid signalling and allow for corticosteroid-mediated potentiation of alpha-adrenergic receptor signalling. Such augmentation of cardiomyocyte hypertrophy may in part explain the role that corticosteroid hormones play in the pathophysiological progression of heart disease.