Abstract 10006: Oxidative Stress Promotes Glucocorticoid-induced Cardiac Fibrosis Mediated by Mineralocorticoid Receptor and Its Co-activator
Backgrounds: Cardiac fibrosis is considered to be a key determinant in the development of heart failure (HF). We reported that mineralocorticoid receptor (MR) antagonist eplerenone reduced cardiac fibrosis and prevented overt heart failure in a rat model of HF. Although production of reactive oxygen species was enhanced and corticosterone levels were extremely higher than aldosterone levels in the left ventricles of the HF rats, it is still unclear whether corticosterone works as MR agonist in the progression of cardiac fibrosis under oxidative stress. In this study, we investigated corticosterone-induced cardiac fibrosis through MR under oxidative stress and contribution of a co-activator of MR to the glucocorticoid-MR pathway.
Methods and Results: Dahl salt-sensitive rats fed high-salt diet were used as HF model. Cardiac fibrosis was enhanced in the left ventricles of the HF rats accompanied by enhanced oxidative stress and increased expression levels of the MR co-activator. H2O2 treatment as oxidative stress also increased the expression levels of the MR co-activator in cultured cardiac fibroblasts. Corticosterone increased collagen production, evaluated by measuring [3H]proline incorporation, in cultured cardiac fibroblasts. This corticosterone-induced collagen production was not attenuated by eplerenone in the absence of H2O2, but attenuated by eplerenone in the presence of H2O2. Knock-down of the MR co-activator using siRNA blunted this attenuating effect of eplerenone in the presence of H2O2.
Conclusions: In this study, it was revealed that corticosterone can promote cardiac fibrosis through MR. Oxidative stress modulates MR response to corticosterone by increasing the expression levels of the MR co-activator. The MR co-activator is a promising therapeutic target for HF, and preventing cardiac fibrosis by modulating glucocorticoid-MR pathway may become a new therapeutic strategy for HF.
- © 2012 by American Heart Association, Inc.