OBJECTIVES: We investigated whether adrenal betaarrestin 1 (betaarr1)-mediated aldosterone production plays any role in post-MI HF progression.
BACKGROUND: Heart failure (HF) represents one of the most significant health problems worldwide and new and innovative treatments are needed. Aldosterone contributes significantly to HF progression after myocardial infarction (MI) by accelerating adverse cardiac remodeling and ventricular dysfunction. It is produced by the adrenal cortex after angiotensin II (AngII) activation of AngII type 1 receptors (AT1Rs), G protein-coupled receptors (GPCRs) that also signal independently of G proteins. G protein-independent signaling is mediated by betaarrestin (betaarr) -1 and -2. We recently reported that adrenal betaarr1 promotes AT1R-dependent aldosterone production leading to elevated circulating aldosterone levels in vivo.
METHODS: Adrenal-targeted, adenoviral-mediated gene delivery in vivo in two-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 betaarr1 or inhibit its function via expression of a betaarr1 C-terminal-derived peptide fragment.
RESULTS: We found that adrenal betaarr1 overexpression promotes aldosterone elevation post-MI, resulting in accelerated cardiac adverse remodeling and deterioration of ventricular function. Importantly, these detrimental effects of aldosterone are prevented when adrenal betaarr1 is inhibited in vivo, which markedly decreases circulating aldosterone post-MI. Finally, the prototypic AT1R antagonist losartan appears unable to lower this adrenal betaarr1-driven aldosterone elevation.
CONCLUSIONS: Adrenal betaarr1 inhibition, either directly or with AT1R “biased” antagonists that prevent receptor-betaarr1 coupling, might be of therapeutic value for curbing HF-exacerbating hyperaldosteronism.
Recommended CitationLymperopoulos, PhD, Anastasios; Rengo, MD, Giuseppe; Zincarelli, MD, Carmela; Kim, PhD, Jihee; and Koch, PhD, Walter J., "Adrenal beta-arrestin 1 inhibition in vivo attenuates post-myocardial infarction progression to heart failure and adverse remodeling via reduction of circulating aldosterone levels" (2011). Center for Translational Medicine Faculty Papers. Paper 6.