Abstract
Mineralocorticoid antagonists have been shown to be useful in the treatment of severe heart failure and may even save lives in this context. However, the reason for the beneficial action of these drugs, as well as the physiological role played by the cardiac mineralocorticoid receptor (MR), are still poorly understood. While the proinflammatory action of aldosterone on the heart and the resulting fibrosis partly explain the improvement due to the anti-mineralocorticoid therapy, the reduction in sudden death is probably related to a lower occurrence of ventricular arrhythmias. In this review, the author explains the physiological mechanism linking the positive chronotropic response induced by aldosterone observed in vitro with isolated ventricular cardiomyocytes and the increased risk of ventricular arrhythmias reported in vivo in hyperaldosteronism. He describes the molecular steps involved between MR activation and acceleration of spontaneous myocyte contractions, including expression of a specific micro RNA (miR204), down-regulation of a silencing transcription factor (NRSF), and re-expression of a fetal gene encoding a low threshold voltage-gated calcium channel (CaV3.2). Finally, he provides evidence suggesting aldosterone-independent and redox-sensitive mechanisms of MR activation in cardiac myocytes. Taken together, this information suggests that the use of anti-mineralocorticoid therapy could benefit the heart by preventing ventricular arrhythmias, not only in established hyperaldosteronism, but also in various pathological situations such as Cushing’s disease, oxidative stress, or even diabetes mellitus.
Highlights
The mineralocorticoid receptor (MR), called aldosterone receptor, is a nuclear receptor of the subfamily 3 (NR3C2), a group of proteins comprising the receptors for steroid hormones
This protein appears constitutively expressed in cardiac cells and abolished by both aldosterone and micro RNA 204 (miR-204), while its messenger RNA remains unaffected by these treatments, a feature typical of the action exerted by micro RNAs [21]
While the exact role of MR in the latter remains to be elucidated, overstimulation of this receptor can lead to deleterious conditions, such as tissue inflammation, fibrosis, and apoptosis, as well as, in the case of the heart, to electrical remodeling and hypertrophy
Summary
The mineralocorticoid receptor (MR), called aldosterone receptor, is a nuclear receptor of the subfamily 3 (NR3C2), a group of proteins comprising the receptors for steroid hormones. Sodium reabsorption induced by MR, if inappropriate, results in increased blood pressure and high risk of hypokalemia For this reason, synthetic MR antagonists, both steroidal (spironolactone, canrenone, eplerenone) and non-steroidal drugs (apararenone, esaxerenone, finerenone), have been developed for preventing adverse effects of aldosterone excess. The nature of the MR endogenous ligand in older species like fishes, as well as the function of this receptor in the heart, are still a matter of debate [13] The aims of this mini-review are discussing a recently developed molecular model for linking the activation of the cardiac MR to the electrical remodeling of the cardiomyocytes responsible for the increased risk of ventricular arrhythmias, and discussing the nature of the ligand(s) and mechanisms leading to receptor stimulation. When isolated neonate rat ventricular cardiomyocytes, maintained in primary culture, are exposed to exogenous aldosterone, one can observe a strong and robust acceleration
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