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 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.
Lymperopoulos
Anastasios
A
Center for Translational Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Rengo
Giuseppe
G
Funakoshi
Hajime
H
Eckhart
Andrea D
AD
Koch
Walter J
WJ
D000311:Adrenal Glands / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D000308:Adrenocortical Hyperfunction / Q000201:enzymology* / Q000503:physiopathology; D000818:Animals; D002478:Cells, Cultured; D054769:G-Protein-Coupled Receptor Kinase 2; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006333:Heart Failure / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000502:physiology*; D051552:beta-Adrenergic Receptor Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000502:physiology
C496568:GRK2 protein, mouse; C496569:Grk2 protein, rat; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2