title: Aldosterone signaling associates with p300/GATA4 transcriptional pathway during the hypertrophic response of cardiomyocytes.
abstract: BACKGROUND
  Aldosterone exerts its effect by binding to specific mineralocorticoid receptors (MRs). Spironolactone blocks the aldosterone system, which ameliorates heart failure in humans, but the precise molecular mechanisms of MR blockade are unclear.
  
  
  RESULTS
  Neonatal rat cardiomyocytes were stimulated with phenylephrine (PE), aldosterone, and/or spironolactone. The association of the MR with p300, a transcriptional coactivator of GATA4 required for hypertrophic responses, was examined. MR and p300 synergistically activated GATA4-dependent atrial natriuretic factor (ANF) promoter activities. The stimulation of cardiomyocytes with PE induced translocation of the MRs into the nuclei and markedly increased the association of MRs with p300. Compatible with the synergistic activation by the MR and p300, aldosterone further augmented the PE-induced increase in cell size and induction of ANF gene transcription. Blockade of MR activation by spironolactone inhibited the PE-induced nuclear translocation of MRs and hypertrophic responses.
  
  
  CONCLUSIONS
  For the first time it has been demonstrated that the aldosterone/MR system associates with the p300/GATA4 transcriptional pathway during the hypertrophic response of cardiomyocytes, and may provide a mechanism of the beneficial effects of aldosterone-blocking agents in heart failure therapy in humans. (Circ J 2010; 74: 156 - 162).
authors: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan.
authors: Yoshinori
authors: Y
authors: Yoshida
authors: Tatsuya
authors: T
authors: Morimoto
authors: Tomohide
authors: T
authors: Takaya
authors: Teruhisa
authors: T
authors: Kawamura
authors: Yoichi
authors: Y
authors: Sunagawa
authors: Hiromichi
authors: H
authors: Wada
authors: Masatoshi
authors: M
authors: Fujita
authors: Akira
authors: A
authors: Shimatsu
authors: Toru
authors: T
authors: Kita
authors: Koji
authors: K
authors: Hasegawa
mesh_terms: D000450:Aldosterone / Q000009:adverse effects / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D050991:GATA4 Transcription Factor / Q000378:metabolism*; D006984:Hypertrophy / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D051379:Mice; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D041681:NIH 3T3 Cells; D010656:Phenylephrine / Q000009:adverse effects / Q000494:pharmacology; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013148:Spironolactone / Q000494:pharmacology; D014162:Transfection
chemical_list: D050991:GATA4 Transcription Factor; C084365:Gata4 protein, rat; D018161:Receptors, Mineralocorticoid; D010656:Phenylephrine; D013148:Spironolactone; D000450:Aldosterone; D009320:Atrial Natriuretic Factor; D050881:E1A-Associated p300 Protein; C494362:Ep300 protein, rat