Abstract: | BackgroundCardiac fibrosis is considered to be a crucial factor in the development of heart failure. Blockade of
the mineralocorticoid receptor (MR) attenuated cardiac fibrosis and improved the prognosis of
patients with chronic heart failure but the ligand for MR and the regulatory mechanism of MR pathway
in the diseased heart are unclear. Here, we investigated whether glucocorticoids can promote cardiac
fibrosis through MR in oxidative stress and the involvement of elongation factor eleven-nineteen
lysine-rich leukemia (ELL), a co-activator of MR, in this pathway.Methods and ResultsThe MR antagonist eplerenone attenuated corticosterone-induced collagen synthesis assessed by
3H]proline incorporation in rat neonatal cultured cardiac fibroblasts in the presence of
H2O2, as an oxidative stress but not in the absence of H2O2.
H2O2 increased the ELL expression levels and MR-bound ELL. ELL expression levels and
MR-bound ELL were also increased in the left ventricle of heart failure model rats with significant
fibrosis and enhanced oxidative stress. Eplerenone did not attenuate corticosterone-induced increase of
3H]proline incorporation in the presence of H2O2 after knockdown of ELL
expression using small interfering RNA in cardiac fibroblasts.ConclusionGlucocorticoids can promote cardiac fibrosis via MR in oxidative stress, and oxidative stress modulates
MR response to glucocorticoids through the interaction with ELL. Preventing cardiac fibrosis by modulating
glucocorticoid-MR-ELL pathway may become a new therapeutic strategy for heart failure. |