Aldosterone signaling associates with p300/GATA4 transcriptional pathway during the hypertrophic response of cardiomyocytes.
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).
Yoshida
Yoshinori
Y
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan.
Morimoto
Tatsuya
T
Takaya
Tomohide
T
Kawamura
Teruhisa
T
Sunagawa
Yoichi
Y
Wada
Hiromichi
H
Fujita
Masatoshi
M
Shimatsu
Akira
A
Kita
Toru
T
Hasegawa
Koji
K
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
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