Blockade of β‐adrenoceptors restores the GRK2‐mediated adrenal α₂‐adrenoceptor–catecholamine production axis in heart failure

Abstract

BACKGROUND AND PURPOSE Sympathetic nervous system (SNS) hyperactivity is characteristic of chronic heart failure (HF) and significantly worsens prognosis. The success of β‐adrenoceptor antagonist (β‐blockers) therapy in HF is primarily attributed to protection of the heart from the noxious effects of augmented catecholamine levels. β‐Blockers have been shown to reduce SNS hyperactivity in HF, but the underlying molecular mechanisms are not understood. The GPCR kinase‐2 (GRK2)–α2adrenoceptor–catecholamine production axis is up‐regulated in the adrenal medulla during HF causing α2‐adrenoceptor dysfunction and elevated catecholamine levels. Here, we sought to investigate if β‐blocker treatment in HF could lower SNS activation by directly altering adrenal GRK2 levels. EXPERIMENTAL APPROACH Four weeks after myocardial infarction‐induced HF, adult rats were randomized to 10‐week treatment with vehicle (HF/C) or bisoprolol (HF/B). Cardiac function and dimensions were measured. In heart and adrenal gland, GRK2 levels were assessed by RT‐PCR and Western blotting and adrenoceptors studied with radioligand binding. Catecholamines and α2adrenoceptors in adrenal medulla chromaffin cell cultures were also measured. KEY RESULTS Bisoprolol treatment ameliorated HF‐related adverse cardiac remodelling and reduced plasma catecholamine levels, compared with HF/C rats. Bisoprolol also attenuated adrenal GRK2 overexpression as observed in HF/C rats and increased α2adrenoceptor density. In cultures of adrenal medulla chromaffin cells from all study groups, bisoprolol reversed HF‐related α2adrenoceptor dysfunction. This effect was reversed by GRK2 overexpression. CONCLUSION AND IMPLICATIONS Blockade of β‐adrenoceptors normalized the adrenal α2adrenoceptor‐catecholamine production axis by reducing GRK2 levels. This effect may contribute significantly to the decrease of HF‐related sympathetic overdrive by β−blockers.

Adrenergic Nervous System in Heart Failure

“…2). 81–85 This emerging crucial role for adrenal GRK2 in HF is underlined by the fact that its specific inhibition, via adenoviral-mediated βARKct adrenal gene delivery (see below), leads to a significant reduction in circulating catecholamine levels, restoring not only adrenal, but also cardiac function in HF. 81 Additional evidence for the crucial role of adrenal GRK2-regulated α 2 ARs in regulating adrenal ANS tone in HF comes from the phenylethanolamine-N-methyl transferase (PNMT)-driven GRK2 KO mice.…”

“…121 In addition, restoration of adrenal GRK2-α 2 AR-catecholamine secretion axis and suppression of NE release from cardiac ANS endings might contribute to the beneficial effects of β-blockers in chronic HF, as well. 74,85 …”

The expanding GRK interactome: Implications in cardiovascular disease and potential for therapeutic development

“…Interestingly, exercise in HF was also found to not only improve GRK2 levels and β-AR signaling in the heart, but also lead to reduction of GRK2 levels in the adrenal gland supporting the notion that these sympatholytic effects can improve cardiac responses [78]. β-blockers also appear to have the capacity to lower GRK2 levels in both the heart and the adrenal gland, which appears critical to any sympatholytic effect of this HF therapy [79]. …”

Tailoring therapy for heart failure: the pharmacogenomics of adrenergic receptor signaling

“…Indeed, recent studies have demonstrated that β-blockers can ameliorate clinical outcomes in HF also by reducing adrenal GRK2 levels, thus normalizing catecholamine release by restoring the negative feedback mediated by α2AR (bisoprolol)32 or by increasing vascular endothelial growth factor signaling, thus stimulating neoangiogenesis (atenolol and bisoprolol) 33…”