Aldosterone inhibits the fetal program and increases hypertrophy in the heart of hypertensive mice.
BACKGROUND
Arterial hypertension (AH) induces cardiac hypertrophy and reactivation of "fetal" gene expression. In rodent heart, alpha-Myosin Heavy Chain (MyHC) and its micro-RNA miR-208a regulate the expression of beta-MyHC and of its intronic miR-208b. However, the role of aldosterone in these processes remains unclear.


RESULTS
RT-PCR and western-blot were used to investigate the genes modulated by arterial hypertension and cardiac hyperaldosteronism. We developed a model of double-transgenic mice (AS-Ren) with cardiac hyperaldosteronism (AS mice) and systemic hypertension (Ren). AS-Ren mice had increased (x2) angiotensin II in plasma and increased (x2) aldosterone in heart. Ren and AS-Ren mice had a robust and similar hypertension (+70%) versus their controls. Anatomical data and echocardiography showed a worsening of cardiac hypertrophy (+41%) in AS-Ren mice (P<0.05 vs Ren). The increase of ANP (x 2.5; P<0.01) mRNA observed in Ren mice was blunted in AS-Ren mice. This non-induction of antitrophic natriuretic peptides may be involved in the higher trophic cardiac response in AS-Ren mice, as indicated by the markedly reduced cardiac hypertrophy in ANP-infused AS-Ren mice for one month. Besides, the AH-induced increase of ßMyHC and its intronic miRNA-208b was prevented in AS-Ren. The inhibition of miR 208a (-75%, p<0.001) in AS-Ren mice compared to AS was associated with increased Sox 6 mRNA (x 1.34; p<0.05), an inhibitor of ßMyHC transcription. Eplerenone prevented all aldosterone-dependent effects.


CONCLUSIONS
Our results indicate that increased aldosterone in heart inhibits the induction of atrial natriuretic peptide expression, via the mineralocorticoid receptor. This worsens cardiac hypertrophy without changing blood pressure. Moreover, this work reveals an original aldosterone-dependent inhibition of miR-208a in hypertension, resulting in the inhibition of β-myosin heavy chain expression through the induction of its transcriptional repressor Sox6. Thus, aldosterone inhibits the fetal program and increases cardiac hypertrophy in hypertensive mice.
Unit 942 INSERM and Université Paris-Diderot, Paris, France.
Feriel
F
Azibani
Yvan
Y
Devaux
Guillaume
G
Coutance
Saskia
S
Schlossarek
Evelyne
E
Polidano
Loubina
L
Fazal
Regine
R
Merval
Lucie
L
Carrier
Alain Cohen
AC
Solal
Christos
C
Chatziantoniou
Jean-Marie
JM
Launay
Jane-Lise
JL
Samuel
Claude
C
Delcayre
D000450:Aldosterone / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D006332:Cardiomegaly / Q000150:complications* / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006929:Hyperaldosteronism / Q000150:complications; D006973:Hypertension / Q000150:complications*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D045265:Natriuretic Peptides / Q000235:genetics / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D017362:Cyclic AMP Response Element-Binding Protein; D035683:MicroRNAs; C551613:Myh7 protein, mouse; D045265:Natriuretic Peptides; D010750:Phosphoproteins; D000450:Aldosterone; D018995:Myosin Heavy Chains