REGULATION OF ALDOSTERONE LEVELS BY ADRENAL …



REGULATION OF ALDOSTERONE LEVELS BY ADRENAL BETAARRESTIN-1 AS A NEW MOLECULAR TARGET IN HEART FAILURE

A. Lymperopoulos1,2, G. Rengo2,3, W.J. Koch2

1College of Pharmacy, Nova Southeastern University, Ft. Lauderdale, FL, USA2George Zallie and Family Laboratory for Cardiovascular Gene Therapy, Center for Translational Medicine, Thomas Jefferson University, Philadelphia, PA, USA, 3University of Naples Federico II, Naples, Italy

Objective(s): To delineate whether inhibition of adrenal betaarrestin-1 (betaarr1)-mediated hyperaldosteronism ameliorates heart failure (HF) progression post-myocardial infarction (MI).

Background: Aldosterone is one of the various hormones with detrimental functions for the failing heart, whose circulating levels are elevated in chronic HF. It is produced and secreted by the adrenal cortex in response to angiotensin II (AngII) acting through AngII type 1 receptors (AT1Rs), G-protein coupled or heptahelical receptors (GPCRs or 7TMRs) that also signal through G protein-independent pathways. The scaffolding actions of betaarr1 and -2, originally discovered as terminators of GPCR signaling, have a central role in mediating this G-protein-independent signal transduction by AT1Rs. We recently reported that betaarr1 promotes AT1R-dependent aldosterone production through sustained extracellular signal-regulated kinase (ERK) activation and steroidogenic acute regulatory (StAR) protein upregulation in vitro and in vivo.

Methods: 2-week post-MI rats progressing to HF were used for in vivo direct intra-adrenal injection of adenoviral betaarr1-related genetic constructs and effects on aldosterone levels and cardiac function were assessed one week later.

Results: Elevated adrenal betaarr1 levels increase circulating aldosterone in post-MI rats, resulting in accelerated adverse remodeling and deterioration of cardiac function. These effects are fully prevented by adrenal betaarr1 inhibition in vivo via a betaarr1 carboxyl-terminal-derived fragment mini-gene (betaarr1ct), which prevents betaarr1 from binding other signal transducing proteins. Additionally, losartan fails to suppress this adrenal betaarr1-mediated hyperaldosteronism post-MI in vivo.

Conclusions: Adrenal betaarr1 inhibition, either directly or with AT1R “biased” antagonists that prevent receptor-betaarr1 coupling, might be of therapeutic value for curbing HF-related hyperaldosteronism.

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