title: Glucocorticoids Induce Cardiac Fibrosis via Mineralocorticoid Receptor in Oxidative Stress: Contribution of Elongation Factor Eleven-Nineteen Lysine-Rich Leukemia (ELL).
abstract: BACKGROUND
  Cardiac 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.
  
  
  RESULTS
  The MR antagonist eplerenone attenuated corticosterone-induced collagen synthesis assessed by [(3)H]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 [(3)H]proline incorporation in the presence of H2O2 after knockdown of ELL expression using small interfering RNA in cardiac fibroblasts.
  
  
  CONCLUSIONS
  Glucocorticoids 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.
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Omori
authors.affiliation: †Cardiovascular Division, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 663-8501, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Mano
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
authors.forename: Tomohito
authors.initials: T
authors.lastname: Ohtani
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakata
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Takeda
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Tamaki
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Tsukamoto
authors.affiliation: ‡Genome Information Research Center, Osaka University, Suita 565-0871, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Miwa
authors.affiliation: §Division of Molecular Medicine and Therapeutics, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: ¶Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku 113-0033, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
keywords: co-activator; corticosterone; eplerenone; heart failure