Journal
NATURE MEDICINE
Volume 13, Issue 3, Pages 315-323Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm1553
Keywords
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Funding
- NHLBI NIH HHS [P01-HL075443, R01 HL61690, R01 HL56205] Funding Source: Medline
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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 beta-adrenergic receptor (bAR) antagonists in heart failure argues for SNS hyperactivity being pathogenic; however, sympatholytic agents targeting alpha(2)AR-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 alpha(2)AR 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 a2AR dysregulation in heart failure, resulting in lowered plasma catecholamine levels, improved cardiac bAR signaling and function, and increased sympatholytic efficacy of a a2AR 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.
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