Cardiac steroidogenesis and glucocorticoid in the development of cardiac hypertrophy during the progression to heart failure

Abstract

Elevated plasma glucocorticoid level is an independent predictor of increased mortality risk in chronic heart failure, but local biosynthesis and pathophysiological roles of glucocorticoids in the heart remain unclear. Dahl salt-sensitive rats on high-salt diet and mice with transthoracic aortic banding (TAC) operation (TAC mice), both of which finally represent heart failure, were assessed at compensatory hypertrophic stage. As a model of cardiac-specific activation of steroidogenesis, alpha-myosin heavy chain-steroidogenic acute regulatory protein transgenic mice were used. In hypertrophied hearts of Dahl salt-sensitive rats and TAC mice, the gene expressions of steroidogenic acute regulatory protein and CYP11A, rate limiting factors of steroid biosynthesis, were significantly upregulated and cardiac corticosterone level was increased compared with age-matched control. Although transgenic mice represented no morphological changes at basal condition, TAC induced greater increases in a ratio of left ventricular weight to body weight (4.8 +/- 0.2 vs.4.3 +/- 0.1 mg/g, P < 0.05) and left ventricular corticosterone level (104.5 +/- 13.3 vs. 69.8 +/- 3.8 pg/mg, P < 0.05) in the transgenic mice than in littermates. In neonatal cardiomyocytes, corticosterone increased atrial natriuretic peptide expression, protein synthesis and cell surface area, and provided the additive hypertrophic effects on phenylephrine-induced hypertrophied myocytes. These effects were prevented by glucocorticoid receptor blockade but not by mineralocorticoid receptor blockade. In hypertrophied hearts, cardiac steroidogenesis was activated with an increase in cardiac glucocorticoid level. Glucocorticoid had potential of augmenting cardiac hypertrophy via glucocorticoid receptor even under the activation of alpha-adrenoceptor-mediated hypertrophic signaling. Cardiac steroidogenesis system and local glucocorticoid may play important roles in the development of hypertrophy and the progression to heart failure.