Adrenal beta-arrestin 1 inhibition in vivo attenuates post-myocardial infarction progression to heart failure and adverse remodeling via reduction of circulating aldosterone levels.

OBJECTIVES: We investigated whether adrenal beta-arrestin 1 (βarr1)-mediated aldosterone production plays any role in post-myocardial infarction (MI) heart failure (HF) progression.
BACKGROUND: Heart failure represents 1 of the most significant health problems worldwide, and new and innovative treatments are needed. Aldosterone contributes significantly to HF progression after MI by accelerating adverse cardiac remodeling and ventricular dysfunction. It is produced by the adrenal cortex after angiotensin II activation of angiotensin II type 1 receptors (AT₁Rs), G protein-coupled receptors that also signal independently of G proteins. The G protein-independent signaling is mediated by βarr1 and βarr2. We recently reported that adrenal βarr1 promotes AT₁R-dependent aldosterone production leading to elevated circulating aldosterone levels in vivo.
METHODS: Adrenal-targeted, adenoviral-mediated gene delivery in vivo in 2-week post-MI rats, a time point around which circulating aldosterone significantly increases to accelerate HF progression, was performed to either increase the expression of adrenal βarr1 or inhibit its function via expression of a βarr1 C-terminal-derived peptide fragment.
RESULTS: We found that adrenal βarr1 overexpression promotes aldosterone elevation after MI, resulting in accelerated cardiac adverse remodeling and deterioration of ventricular function. Importantly, these detrimental effects of aldosterone are prevented when adrenal βarr1 is inhibited in vivo, which markedly decreases circulating aldosterone after MI. Finally, the prototypic AT₁R antagonist losartan seems unable to lower this adrenal βarr1-driven aldosterone elevation.
CONCLUSIONS: Adrenal βarr1 inhibition, either directly or with AT₁R "biased" antagonists that prevent receptor-βarr1 coupling, might be of therapeutic value for curbing HF-exacerbating hyperaldosteronism. Copyright Â