Atrial Natriuretic Peptide Locally Counteracts the Deleterious Effects of Cardiomyocyte Mineralcorticoid Receptor Activation
Background—The endocrine balance between atrial natriuretic peptide (ANP) and the renin-angiotensin-aldosterone system is critical for the maintenance of arterial blood pressure and volume homeostasis. This study investigated whether a cardiac imbalance between ANP and aldosterone, towards increased mineralcorticoid receptor (MR) signaling, contributes to adverse left ventricular (LV) remodeling in response to pressure overload.
Methods and Results—We used the MR-selective antagonist eplerenone to test the role of MRs in mediating pressure overload-induced dilatative cardiomyopathy of mice with abolished local, cardiac ANP activity. In response to 21-days of transverse aortic constriction (TAC), mice with cardiomyocyte-restricted inactivation (KO) of the ANP receptor (guanylyl cyclase (GC)-A) or the downstream cGMP-dependent protein kinase I (cGKI) developed enhanced LV hypertrophy and fibrosis together with contractile dysfunction. Treatment with eplerenone (100 mg/kg/day) attenuated LV hypertrophy and fully prevented fibrosis, dilatation and failure. TAC induced the cardiac expression of profibrotic CTGF and attenuated the expression of SERCA2a in KO mice, but not in controls. These genotype-dependent molecular changes were similarly prevented by eplerenone. ANP attenuated the aldosterone-induced nuclear translocation of MRs via GC-A/cGKI in transfected HEK 293 cells. Co-immunoprecipitation and FRET experiments demonstrated that a population of MRs were membrane-associated in close interaction with GC-A and cGKI, and moreover, that aldosterone caused a conformational change of this membrane MR/GC-A protein complex which was prevented by ANP.
Conclusions—ANP counterregulates cardiac MR activation in hypertensive heart disease. An imbalance in cardiac ANP/GC-A (inhibition) and aldosterone/MR signaling (augmentation) favors adverse cardiac remodeling in chronic pressure overload.
- Received October 4, 2013.
- Accepted June 30, 2014.