SignalingP513Aldosterone inhibits Akt and Calcineurin pathways in hypertension-induced hypertrophy

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Abstract

The adult myocardium responds to arterial hypertension (AH) by a hypertrophic response and reactivation of the "fetal" gene program. In rodent heart,alpha-Myosin Heavy Chain (MyHC) and its micro-RNA miR-208a regulates the expression of beta-MyHC (Myh7) and of its intronic miR-208b. We aimed to investigate the hypertrophic pathways induced by AH and cardiac hyperaldosteronism.

We developed a model of double-transgenic mice (AS-Ren) with cardiac hyperaldosteronism (AS mice) and systemic hypertension (Ren).

Both Ren and AS-Ren mice had a robust and similar AH (p < 0.005 versusWT and AS). Echocardiography showed an increased LV mass ( + 50%;p < 0.05 vs WT) in AS-Ren mice compared to WT . This LV-hypertrophy was confirmed by an increase of HW/BW ratio in Ren mice ( + 20% ± 6; P < 0.05 vs WT), that was enhancedin AS-Ren ( + 41% ± 6; P < 0.05vs Ren).

The Serum Response Factor was equally upregulated in Ren and AS-Ren mice (x1.4;p < 0.05 vs controls), its target gene the skeletal-actin was also induced (x6.1; p < 0.001) in both AH groups. The physiological hypertrophic pathway Akt was inhibited in AS-Ren mice (p-Akt/total Akt: -60%;p < 0.05 vs AS and -27%; p < 0.05vs Ren) and downstream Akt, calcineurin inhibitor Atrogin-1 was induced (x1.3; p < 0.05) in AS-Ren mice. In line with Atrogin-1 , we observed a non-activation of calcineurin pathway, as revealed by the specific down-regulation of MCIP-1 transcription in AS-Ren in contrast to Ren mice (-30%,p < 0.05 vs. Ren).

Then we analysed the expression of calcineurin-NFAT target genes such as BNP, ANP and MyHC7. Interestingly, BNP, ANP and MyHC7expressions were blunted in AS-Ren mice, whereas both transcripts were upregulated in Ren mice (x 2.5;p < 0.01). The non-induction of antitrophic natriuretic peptides may be involved in the higher trophic cardiac response in AS-Ren mice. Sox6 mRNA, MyHC7 transcription repressor, was specifically induced in AS-Ren mice (x1.34; p < 0.05 vs Ren) through the inhibition of miR-208a (-70%; p < 0.001 in AS-Ren vs Ren mice). In addition, the expression of miR-208b followed the same profile than MyHC7 expression. Thus, the non-induction of MyHC7 in AS-Ren results from inhibition of both calcineurin and Sox6 pathways. Of note, eplerenone treatment reversed the AS-Ren mouse transcription profile towards Ren phenotype with up-regulation of BNP, ANP and MyHC7 mRNAs.

The data indicate that in a context of AH, a cardiac hyperaldosteronism inhibits the Akt activation through MR-dependant pathways. This inhibition in turn induces increase of Atrogin-1 which inhibits the calcineurin induction. This work thus reveals an original scheme of aldosterone action in hypertension.

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