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European Heart Journal Advance Access originally published online on July 29, 2005
European Heart Journal 2005 26(17):1752-1758; doi:10.1093/eurheartj/ehi429
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© The European Society of Cardiology 2005. All rights reserved. For Permissions, please e-mail: journals.permissions@oupjournals.org

Elevated myocardial and lymphocyte GRK2 expression and activity in human heart failure

Guido Iaccarino1, Emanuele Barbato1,{dagger}, Ersilia Cipolletta1, Vincenzo De Amicis1, Kenneth B. Margulies2,{ddagger}, Dario Leosco1, Bruno Trimarco1,* and Walter J. Koch3,*

1Department of Medicina Clinica Scienze Cardiovascolari ed Immunologiche, Federico II University, Via Pansini 5, 80131 Napoli, Italy
2Department of Medicine (Cardiology), Temple University Medical Center, Philadelphia, PA, USA
3Department of Medicine, Center for Translational Medicine, Thomas Jefferson University, 1025 Walnut Street, Room 410, Philadelphia, PA 19107, USA

Received 25 January 2005; revised 9 June 2005; accepted 30 June 2005; online publish-ahead-of-print 29 July 2005.

* Corresponding authors. Tel: +1 215 955 9982; fax: +1 215 503 5731 (WJK); tel: +39 081 746 2256; fax: +39 081 746 2250 (BT). E-mail address: walter.koch{at}jefferson.edu

See page 1695 for the editorial comment on this article (doi:10.1093/eurheartj/ehi355)

Aims The G protein-coupled receptor kinase-2 (GRK2 or ß-ARK1) regulates ß-adrenergic receptors (ß-ARs) in the heart, and its cardiac expression is elevated in human heart failure (HF). We sought to determine whether myocardial levels and activity of GRK2 could be monitored using white blood cells, which have been used to study cardiac ß-ARs. Moreover, we were interested in determining whether GRK2 levels in myocardium and lymphocytes may be associated with ß-AR dysfunction and HF severity.

Methods and results In myocardial biopsies from explanted failing human hearts, GRK activity was inversely correlated with ß-AR-mediated cAMP production (R2=–0.215, P<0.05, n=24). Multiple regression analysis confirmed that GRK activity participates with ß-AR density to regulate catecholamine-sensitive cAMP responses. Importantly, there was a direct correlation between myocardial and lymphocytes GRK2 activity (R2=0.5686, P<0.05, n=10). Lymphocyte GRK activity was assessed in HF patients with various ejection fractions (EFs) (n=33), and kinase activity was significantly higher in patients with lower EFs and was higher with increasing NYHA class (P<0.001).

Conclusion Myocardial GRK2 expression and activity are mirrored by lymphocyte levels of this kinase, and its elevation in HF is associated with the loss of ß-AR responsiveness and appears to increase with disease severity. Therefore, lymphocytes may provide a surrogate for monitoring cardiac GRK2 in human HF.

Key Words: Heart failure • Prognosis • Receptors • Adrenergic • Beta • Signal transduction • Lymphocytes


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