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Blockade of ?-adrenoceptors restores the GRK2-mediated adrenal ?(2) -adrenoceptor-catecholamine production axis in heart failure.

ABSTRACT: Sympathetic nervous system (SNS) hyperactivity is characteristic of chronic heart failure (HF) and significantly worsens prognosis. The success of ?-adrenoceptor antagonist (?-blockers) therapy in HF is primarily attributed to protection of the heart from the noxious effects of augmented catecholamine levels. ?-Blockers have been shown to reduce SNS hyperactivity in HF, but the underlying molecular mechanisms are not understood. The GPCR kinase-2 (GRK2)-?(2) adrenoceptor-catecholamine production axis is up-regulated in the adrenal medulla during HF causing ?(2) -adrenoceptor dysfunction and elevated catecholamine levels. Here, we sought to investigate if ?-blocker treatment in HF could lower SNS activation by directly altering adrenal GRK2 levels.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 ?(2) adrenoceptors in adrenal medulla chromaffin cell cultures were also measured.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 ?(2) adrenoceptor density. In cultures of adrenal medulla chromaffin cells from all study groups, bisoprolol reversed HF-related ?(2) adrenoceptor dysfunction. This effect was reversed by GRK2 overexpression.Blockade of ?-adrenoceptors normalized the adrenal ?(2) adrenoceptor-catecholamine production axis by reducing GRK2 levels. This effect may contribute significantly to the decrease of HF-related sympathetic overdrive by ?-blockers.

SUBMITTER: Rengo G

PROVIDER: S-EPMC3448904 | biostudies-other | 2012 Aug

REPOSITORIES: biostudies-other

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Blockade of β-adrenoceptors restores the GRK2-mediated adrenal α(2) -adrenoceptor-catecholamine production axis in heart failure.

Rengo G G Lymperopoulos A A Zincarelli C C Femminella Gd G Liccardo D D Pagano G G de Lucia C C Cannavo A A Gargiulo P P Ferrara N N Perrone Filardi P P Koch Wj W Leosco D D

British journal of pharmacology 20120801 8

<h4>Background and purpose</h4>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)-α(2) adreno ...[more]

PMID: 22519418

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Project description:Considerable evidence suggests that calcium/calmodulin-dependent protein kinase II (CaMKII) overactivity plays a crucial role in the pathophysiology of heart failure (HF), a condition characterized by excessive ?-adrenoceptor (?-AR) stimulation. Recent studies indicate a significant cross talk between ?-AR signaling and CaMKII activation presenting CaMKII as a possible downstream mediator of detrimental ?-AR signaling in HF. In this study, we investigated the effect of chronic ?-AR blocker treatment on CaMKII activity in human and experimental HF.Immunoblot analysis of myocardium from end-stage HF patients (n=12) and non-HF subjects undergoing cardiac surgery (n=12) treated with ?-AR blockers revealed no difference in CaMKII activity when compared with non-?-AR blocker-treated patients. CaMKII activity was judged by analysis of CaMKII expression, autophosphorylation, and oxidation and by investigating the phosphorylation status of CaMKII downstream targets. To further evaluate these findings, CaMKII?C transgenic mice were treated with the ?1-AR blocker metoprolol (270 mg/kg*d). Metoprolol significantly reduced transgene-associated mortality (n?29; P<0.001), attenuated the development of cardiac hypertrophy (-14±6% heart weight/tibia length; P<0.05), and strongly reduced ventricular arrhythmias (-70±22% premature ventricular contractions; P<0.05). On a molecular level, metoprolol expectedly decreased protein kinase A-dependent phospholamban and ryanodine receptor 2 phosphorylation (-42±9% for P-phospholamban-S16 and -22±7% for P-ryanodine receptor 2-S2808; P<0.05). However, this was paralled neither by a reduction in CaMKII autophosphorylation, oxidation, and substrate binding nor a change in the phosphorylation of CaMKII downstream target proteins (n?11). The lack of CaMKII modulation by ?-AR blocker treatment was confirmed in healthy wild-type mice receiving metoprolol.Chronic ?-AR blocker therapy in patients and in a mouse model of CaMKII-induced HF is not associated with a change in CaMKII activity. Thus, our data suggest that the molecular effects of ?-AR blockers are not based on a modulation of CaMKII. Directly targeting CaMKII may, therefore, further improve HF therapy in addition to ?-AR blockade.

Dataset Information

Blockade of ?-adrenoceptors restores the GRK2-mediated adrenal ?(2) -adrenoceptor-catecholamine production axis in heart failure.

Publications

Blockade of β-adrenoceptors restores the GRK2-mediated adrenal α(2) -adrenoceptor-catecholamine production axis in heart failure.

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