Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure

Nat Med. 2007 Mar;13(3):315-23. doi: 10.1038/nm1553. Epub 2007 Feb 18.


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 (betaAR) antagonists in heart failure argues for SNS hyperactivity being pathogenic; however, sympatholytic agents targeting alpha2AR-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 alpha2AR 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 alpha2AR dysregulation in heart failure, resulting in lowered plasma catecholamine levels, improved cardiac betaAR signaling and function, and increased sympatholytic efficacy of a alpha2AR 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Glands / enzymology*
  • Adrenal Glands / pathology
  • Adrenal Glands / physiopathology
  • Adrenocortical Hyperfunction / enzymology*
  • Adrenocortical Hyperfunction / physiopathology
  • Animals
  • Cells, Cultured
  • G-Protein-Coupled Receptor Kinase 2
  • Gene Expression Regulation, Enzymologic / physiology*
  • Heart Failure / enzymology*
  • Heart Failure / physiopathology
  • Male
  • Mice
  • Mice, Transgenic
  • Rats
  • Rats, Sprague-Dawley
  • Up-Regulation / physiology*
  • beta-Adrenergic Receptor Kinases / antagonists & inhibitors
  • beta-Adrenergic Receptor Kinases / biosynthesis*
  • beta-Adrenergic Receptor Kinases / physiology


  • GRK2 protein, mouse
  • Grk2 protein, rat
  • beta-Adrenergic Receptor Kinases
  • G-Protein-Coupled Receptor Kinase 2