title: Elevated myocardial and lymphocyte GRK2 expression and activity in human heart failure.
abstract: OBJECTIVE
  The G protein-coupled receptor kinase-2 (GRK2 or beta-ARK1) regulates beta-adrenergic receptors (beta-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 beta-ARs. Moreover, we were interested in determining whether GRK2 levels in myocardium and lymphocytes may be associated with beta-AR dysfunction and HF severity.
  
  
  RESULTS
  In myocardial biopsies from explanted failing human hearts, GRK activity was inversely correlated with beta-AR-mediated cAMP production (R(2)=-0.215, P<0.05, n=24). Multiple regression analysis confirmed that GRK activity participates with beta-AR density to regulate catecholamine-sensitive cAMP responses. Importantly, there was a direct correlation between myocardial and lymphocytes GRK2 activity (R(2)=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).
  
  
  CONCLUSIONS
  Myocardial GRK2 expression and activity are mirrored by lymphocyte levels of this kinase, and its elevation in HF is associated with the loss of beta-AR responsiveness and appears to increase with disease severity. Therefore, lymphocytes may provide a surrogate for monitoring cardiac GRK2 in human HF.
authors.affiliation: Department of Medicina Clinica Scienze Cardiovascolari ed Immunologiche, Federico II University, Via Pansini 5, 80131 Naples, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Iaccarino
authors.forename: Emanuele
authors.initials: E
authors.lastname: Barbato
authors.forename: Ersilia
authors.initials: E
authors.lastname: Cipolletta
authors.forename: Vincenzo
authors.initials: V
authors.lastname: De Amicis
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Margulies
authors.forename: Dario
authors.initials: D
authors.lastname: Leosco
authors.forename: Bruno
authors.initials: B
authors.lastname: Trimarco
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis; D005260:Female; D054769:G-Protein-Coupled Receptor Kinase 2; D006333:Heart Failure / Q000201:enzymology* / Q000503:physiopathology / Q000601:surgery; D016027:Heart Transplantation; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000201:enzymology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D012720:Severity of Illness Index; D015398:Signal Transduction; D013318:Stroke Volume; D051552:beta-Adrenergic Receptor Kinases / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; C496567:GRK2 protein, human; D051552:beta-Adrenergic Receptor Kinases; D054769:G-Protein-Coupled Receptor Kinase 2