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.
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Acknowledgements
We thank R. Lefkowitz (Duke University Medical Center) for the antibody to βarrs A1CT and M. Santangelo (University of Naples “Federico II”) for providing the human adrenal gland tissue. We also thank J. Kurt Chuprun for technical advice, R. Kerkela for assistance with immunofluorescence, and S. Soltys, M. Kuhn, R.-H. Zhou, M. Shapiro and C. Zincarelli for technical assistance. This work was supported in part by US National Institutes of Health grants R01 HL61690, R01 HL56205 and P01-HL075443 (to W.J.K.) and a fellowship from the Pennsylvania-Delaware Affiliate of the American Heart Association (to A.L.).
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A.L. conceived the project, conducted all the experiments and wrote the paper. G.R. did the in vivo gene delivery and the echocardiographic and hemodynamic studies. H.F. did the echocardiography in CSQ-Tg mice. A.D.E. contributed to the writing of the paper. W.J.K. supervised the project and wrote the paper.
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Supplementary information
Supplementary Fig. 1
Echocardiographic analysis of 3-month-old NLC and CSQ/Tg mice. (PDF 16 kb)
Supplementary Fig. 2
Basal and isoproterenol-stimulated hemodynamic responses in 3-month-old NLC and CSQ/Tg mice. (PDF 22 kb)
Supplementary Fig. 3
Echocardiographic analysis of HF rats 10 weeks post-MI (HF) and age-matched sham-operated controls (sham). (PDF 16 kb)
Supplementary Fig. 4
α2-ARs and GRK2 are expressed in human adrenal glands. (PDF 270 kb)
Supplementary Fig. 5
Adenoviral-mediated transfection of primary chromaffin cells. (PDF 87 kb)
Supplementary Table 1
In vivo cardiac functional parameters after adrenal gene delivery. (PDF 114 kb)
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Lymperopoulos, A., Rengo, G., Funakoshi, H. et al. Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure. Nat Med 13, 315–323 (2007). https://doi.org/10.1038/nm1553
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DOI: https://doi.org/10.1038/nm1553
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