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

摘要

OBJECTIVES: We investigated whether adrenal beta-arrestin 1 (betaarr1)-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 (ATRs), G protein-coupled receptors that also signal independently of G proteins. The G protein-independent signaling is mediated by betaarr1 and betaarr2. We recently reported that adrenal betaarr1 promotes ATR-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 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 after 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 after MI. Finally, the prototypic ATR antagonist losartan seems unable to lower this adrenal betaarr1-driven aldosterone elevation. CONCLUSIONS: Adrenal betaarr1 inhibition, either directly or with ATR "biased" antagonists that prevent receptor-betaarr1 coupling, might be of therapeutic value for curbing HF-exacerbating hyperaldosteronism.