Aldosterone inhibits the fetal program and increases hypertrophy in the heart of hypertensive mice.

Feriel Azibani,Loubina Fazal,Jane-Lise Samuel,Alain Cohen Solal,Lucie Carrier,Regine Merval,Jean-Marie Launay,Yvan Devaux,Saskia Schlossarek,Evelyne Polidano,Christos Chatziantoniou,Guillaume Coutance,Claude Delcayre,James West

doi:10.1371/journal.pone.0038197

Abstract

BackgroundArterial 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.Methodology/Principal FindingsRT-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/SignificanceOur 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.

Highlights

Cardiac hypertrophy (CH) is a well-known consequence of chronic arterial hypertension
Our results indicate that elevated levels of aldosterone in the heart inhibit natriuretic peptides (NPs) and b-Myosin Heavy Chain (MyHC) expression through original mechanisms
The study was done on 6 and 9 month-old mice in order to study the development of cardiac hypertrophy

Summary

Introduction

Cardiac hypertrophy (CH) is a well-known consequence of chronic arterial hypertension. Aldosterone controls the renal sodium reabsorption, thereby playing a major role in the control of plasma volume. It has emerged in the last years that elevation of plasmatic concentration of aldosterone which occurs in patients with heart failure, is a key-factor of cardiac remodeling [2,3,4] and worsening of cardiac properties. The mechanisms of the deleterious consequences of aldosterone on cardiac functional properties are not totally understood. Arterial hypertension (AH) induces cardiac hypertrophy and reactivation of ‘‘fetal’’ gene expression. The role of aldosterone in these processes remains unclear

Objectives

Methods

Results