Abstract
Current evidence reveals that cardiac mineralocorticoid receptor (MR) activation following myocardial stretch plays an important physiological role in adapting developed force to sudden changes in hemodynamic conditions. Its underlying mechanism involves a previously unknown nongenomic effect of the MR that triggers redox-mediated Na+/H+ exchanger (NHE1) activation, intracellular Na+ accumulation, and a consequent increase in Ca2+ transient amplitude through reverse Na+/Ca2+ exchange. However, clinical evidence assigns a detrimental role to MR activation in the pathogenesis of severe cardiac diseases such as congestive heart failure. This mini review is meant to present and briefly discuss some recent discoveries about locally triggered cardiac MR signals with the objective of shedding some light on its physiological but potentially pathological consequences in the heart.
Highlights
Mineralocorticoids are steroid hormones mainly involved in electrolyte/water balance regulation
We have described a mechanism that comprises a sequential activation of receptors (AT1, ETA, mineralocorticoid receptor (MR), and epidermal growth factor receptor (EGFR)) leading to redox-mediated NHE1 stimulation, which increases intracellular Na+, and Ca2+ transient amplitude through reverse Na+/Ca2+ exchange
An important aspect to elucidate is the exact responsibility for this deleterious activation: ALD, physical deformation of MR, other ligands? No evidence assigns responsibility to ALD for MR activation despite demonstrated direct actions of ALD on the myocardium [5, 36, 51,52,53]
Summary
Mineralocorticoids are steroid hormones mainly involved in electrolyte/water balance regulation. We have demonstrated cancellation of the SFR by MR blockade either pharmacologically [4] or by specific silencing of its expression [37] but not by glucocorticoid antagonism or protein synthesis inhibition [4] These results prove that activated MR is essential to modulate cardiac force response to stretch through a previously undescribed nongenomic effect that involves ROS-mediated NHE1 activation. In the Aldosterone Lethal effects Blockade in Acute myocardial infarction Treated with or without Reperfusion to improve Outcome and Survival at Six months follow-up (ALBATROSS) trial, a single intravenous bolus of potassium canrenoate followed by 6-months oral spironolactone failed to benefit patients admitted for myocardial infarction irrespective of the presence of HF or left ventricular dysfunction [46] These results clearly hamper any general conclusions about efficacy of MR antagonism in HF patients
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