TY - JOUR
T1 - Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure
AU - Lymperopoulos, Anastasios
AU - Rengo, Giuseppe
AU - Funakoshi, Hajime
AU - Eckhart, Andrea D.
AU - Koch, Walter J.
PY - 2007/3
Y1 - 2007/3
N2 - 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.
AB - 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.
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U2 - 10.1038/nm1553
DO - 10.1038/nm1553
M3 - Article
C2 - 17322894
AN - SCOPUS:33847728682
VL - 13
SP - 315
EP - 323
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 3
ER -