A Cardiac Mouse Model for Nongenomic Mineralocorticoid Receptor Effects

Abstract

Aim: As a ligand-dependent transcription factor the mineralocorticoid receptor (MR) regulates water and electrolyte homeostasis in epithelial tissues but also plays a crucial role in the pathogenesis of cardiovascular diseases. In addition to its genomic effects, via the glucocorticoid response elements, rapid interactions with cytosolic signaling cascades have been described, but the physiological or pathophysiological role of this nongenomic MR pathway is still hardly known. Study Design: Transgenic and wild type mice (FVB/N background) of random sex were used in this study. Experimental groups (n = 8-10 for each subgroup) were: A) Cardiac function and gene expression at six months of age; B) Cardiac function and gene expression at twelve months of age; C) Cardiac function at six months of age after 4 weeks aldosterone/NaCl treatment. Place and Duration of Study: Institute for Pharmacology and Toxicology, Medical Faculty of the Martin Luther University Halle-Wittenberg, between June 2008 and November 2011. Methodology: To investigate the cardiac nongenomic MR effects in vivo, we generated a transgenic (TG) mouse model with cardiomyocyte-specific overexpression of a truncated variation of the human MR (hMRDEF). Characterization of six and twelve months old mice focused on cardiac function, electrical activity, and gene transcription under baseline and stimulation conditions by either isoproterenol or aldosterone/NaCl treatment. Results: Whereas overexpression of a full-length MR in the heart was lethal, the phenotype of the hMRDEF-TG mouse seemed inconspicuously. Noteworthy, the nongenomic MR effect modulated the cardiac transcription of the α-subunit of the voltage-gated potassium channel ERG, which resulted in prolonged intraventricular electrical activity. Therefore, nongenomic MR signaling pathways may be responsible for MR-associated cardiac arrhythmias. Conclusion: Our findings demonstrate that nongenomic MR effects can modulate cardiac electrophysiology in vivo and therefore indicate an involvement of nongenomic MR signaling pathways in the pathogenesis of cardiac dysfunction.