Abstract 180: Cardiac Steroidogenesis and Increased Local Corticosterone Contribute to Promoting Cardiac Hypertrophy
Background: Recent reports suggested that glucocorticoid as well as mineralocorticoid may contribute to the progression of heart failure but its local dynamics such as biosynthesis and pathophysiological roles in cardiac tissue were unclear. This study aimed to assess the role of glucocorticoid and local steroid biosynthesis in hypertrophied hearts.
Methods and Results: The mice received transthoracic aortic banding (TAC) operation was used as a cardiac hypertrophy model. In hypertrophied hearts, gene expressions of steroidogenic acute regulatory (StAR) protein and CYP11A, which are rate limiting factors for steroid biosynthesis, were significantly up-regulated. LV tissue level of corticosterone was significantly increased in hypertrophied hearts compared to that of age-matched control (69.8 ± 3.8 vs. 41.7 ± 4.1 pg/mg, p<0.05). Glucocorticoid receptor protein was also increased in hypertrophied hearts. The similar activation of glucocorticoid pathway was observed in another model of cardiac hypertrophy of Dahl hypertensive rats. α-MHC-StAR transgenic mice (TG) were used as a model of cardiac specific activation of steroidogenesis. Though TG had no phenotype in basal condition, TAC-induced increase in LV weight/body weight was greater in TG than operated littermates (non-TG) (4.8 ± 0.2 vs.4.3 ± 0.1mg/g, p<0.05). LV tissue level of corticosterone was higher in TG with TAC than non-TG with TAC (104.5 ± 13.3 vs. 69.8 ± 3.8 pg/mg, p<0.05). In cultured neonatal cardiomyocytes, corticosterone significantly increased ANP expression, protein synthesis and cell surface area. Moreover, corticosterone potentiates hypertrophic effects of phenylephrine and those effects were attenuated by glucocorticoid receptor blockade, but not mineralocorticoid receptor blockade.
Conclusions- In hypertrophied hearts, cardiac steroidogenesis was activated, resulting in the increase in cardiac glucocorticoid contents. Increased tissue glucocorticoid promoted cardiac hypertrophy via glucocorticoid receptor rather than mineralocorticoid receptor.