Background:

Atrial natriuretic peptide (ANP), via its guanylyl cyclase A (GC-A) receptor and cyclic GMP formation, exerts cardiac antihypertrophic/antifibrotic actions. Conversely, aldosterone promotes pathological cardiac remodeling via the mineralocorticoid receptor (MR).

Purpose:

To investigate whether cardiac ANP/GC-A signaling counteracts the effects of aldosterone during experimental hypertensive cardiac remodeling.

Methods and Results:

We studied the impact of the MR antagonist eplerenone (100 mg/kg/day) on cardiac remodeling after transverse aortic constriction (TAC) in mice with conditional, cardiomyocyte-restricted deletion of GC-A (CM GC-A KO) and respective controls (n=10 in each group). Left ventricular (LV) hypertrophy and interstitial fibrosis were significantly exacerbated in CM GC-A KO mice after TAC. These histological changes were accompanied by decreased LV SERCA2a expression together withLV dilatation and dysfunction. Eplerenone had no effect on systemic blood pressure but fully prevented these pressure-overload induced cardiac morphological, molecular and functional alterations in CM GC-A KO mice. Moreover, in transfected HEK 293 cells, ANP inhibited the aldosterone-induced nuclear translocation of the MR.

Conclusion:

ANP, via GC-A/cGMP signaling in cardiac myocytes, attenuates hypertensive cardiac remodeling and dysfunction. These protective ANP effects seem to be mediated at least in part by counterregulation of the deleterious genomic (MR-mediated) cardiac actions of aldosterone.

Supported by the comprehensive heart failure center (CHCF) in Würzburg