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Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure

Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure Cardiac overstimulation by the sympathetic nervous system (SNS) is a salient characteristic of heart failure, reflected by elevated circulating levels of catecholamines. The success of β-adrenergic receptor (βAR) antagonists in heart failure argues for SNS hyperactivity being pathogenic; however, sympatholytic agents targeting α2AR-mediated catecholamine inhibition have been unsuccessful. By investigating adrenal adrenergic receptor signaling in heart failure models, we found molecular mechanisms to explain the failure of sympatholytic agents and discovered a new strategy to lower SNS activity. During heart failure, there is substantial α2AR dysregulation in the adrenal gland, triggered by increased expression and activity of G protein–coupled receptor kinase 2 (GRK2). Adrenal gland–specific GRK2 inhibition reversed α2AR dysregulation in heart failure, resulting in lowered plasma catecholamine levels, improved cardiac βAR signaling and function, and increased sympatholytic efficacy of a α2AR agonist. This is the first demonstration, to our knowledge, of a molecular mechanism for SNS hyperactivity in heart failure, and our study identifies adrenal GRK2 activity as a new sympatholytic target. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Nature Medicine Springer Journals

Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure

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References (51)

Publisher
Springer Journals
Copyright
Copyright © 2007 by Nature Publishing Group
Subject
Biomedicine; Biomedicine, general; Cancer Research; Metabolic Diseases; Infectious Diseases; Molecular Medicine; Neurosciences
ISSN
1078-8956
eISSN
1546-170X
DOI
10.1038/nm1553
Publisher site
See Article on Publisher Site

Abstract

Cardiac overstimulation by the sympathetic nervous system (SNS) is a salient characteristic of heart failure, reflected by elevated circulating levels of catecholamines. The success of β-adrenergic receptor (βAR) antagonists in heart failure argues for SNS hyperactivity being pathogenic; however, sympatholytic agents targeting α2AR-mediated catecholamine inhibition have been unsuccessful. By investigating adrenal adrenergic receptor signaling in heart failure models, we found molecular mechanisms to explain the failure of sympatholytic agents and discovered a new strategy to lower SNS activity. During heart failure, there is substantial α2AR dysregulation in the adrenal gland, triggered by increased expression and activity of G protein–coupled receptor kinase 2 (GRK2). Adrenal gland–specific GRK2 inhibition reversed α2AR dysregulation in heart failure, resulting in lowered plasma catecholamine levels, improved cardiac βAR signaling and function, and increased sympatholytic efficacy of a α2AR agonist. This is the first demonstration, to our knowledge, of a molecular mechanism for SNS hyperactivity in heart failure, and our study identifies adrenal GRK2 activity as a new sympatholytic target.

Journal

Nature Medicine – Springer Journals

Published: Feb 18, 2007

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