Arterial hypertension (AH) is associated with a cardiovascular remodelling in which the Renin-Angiotensin-Aldosterone system plays a key role. Several studies suggest that the cardiac fibrosis that develops during AH results from an imbalance between profibrotic (CTGF, TGFβ, inflammation) and antifibrotic (BNP, BMP4) pathways, in which the role of aldosterone is not yet established. Our aim was to determine, in a context of AH, the role of intracardiac aldosterone in the development of myocardial fibrosis.
We developed a model of double-transgenic mice (AS-Ren) with cardiac hyperaldosteronism (AS mice) and systemic hypertension (Ren mice). Cardiac fibrosis level was 3-fold higher in 9-month old hypertensive mice when compared to control mice, and cardiac hyperaldosteronism further enhanced the fibrosis level. The expression of CTGF (x 1.9; p < 0.05) and TGF-β (x 1.5; p < 0.01) was similarly increased in both Ren and AS-Ren mice compared to WT and AS mice, respectively. However, hyperaldosteronism combined with AH favored the presence of macrophages (Cd68 + cells), enhanced the transcription of MCP-1 (x 1.43; p < 0.01), osteopontin (x 2.6; p < 0.05) and of galectin 3 (P < 0.05) particularly in the fibrotic area. It is noteworthy that galectin 3 expression was related to the preferential expression of collagen 1 versus collagen 3 in AS-Ren mice (x 1.7 and x 0.8 respectively). Besides, the AH-induced BNP was completely blunted in AS-Ren hearts. BMP4 mRNA and protein were significantly inhibited in AS-Ren hearts (-40% and -20% respectively versus Ren). The MR-antagonist eplerenone given for 1 week restored the BNP and BMP4 expressions in AS-Ren mice. The inhibitory effect of aldosterone on BNP and BMP4 was verified in vitro on cultured cardiomyocytes. Finally when AH was induced in WT and AS mice by Ang II infusion for 2 months the mRNA profiles of CD68, CTGF, BNP and BMP4 were similar to those observed in Ren and AS-Ren mice, respectively.
These data demonstrate that a cardiac hyperaldosteronism inhibits the AH-induced expression of the anti-fibrotic factors BNP and BMP4 and thus worsens the AH-associated cardiac fibrosis.