Uncoupling of myocardial beta-adrenergic receptor signaling during coronary artery bypass grafting: the role of GRK2.
BACKGROUND
Cardiopulmonary bypass (CPB) and cardioplegic arrest during cardiac surgery leads to desensitization of myocardial beta-adrenergic receptors (beta-ARs). Impaired signaling through this pathway can have a detrimental effect on ventricular function and increased need for inotropic support. The mechanism of myocardial beta-AR desensitization during cardiac surgery has not been defined. This study investigates the role of G protein-coupled receptor kinase-2 (GRK2), a serine-threonine kinase which phosphorylates and desensitizes agonist-occupied beta-ARs, as a primary mechanism of beta-AR uncoupling during coronary artery bypass grafting (CABG) with CPB and cardioplegic arrest.


METHODS
Forty-eight patients undergoing elective CABG were enrolled in this study. Myocardial beta-AR signaling was assessed by measuring total beta-AR density and adenylyl cyclase activity in right atrial biopsies obtained before CPB and just before weaning from CPB. Myocardial GRK2 expression and activity were also measured before CPB and just before weaning from CPB.


RESULTS
Myocardial beta-AR signaling was significantly impaired after CPB and cardioplegic arrest during CABG. Cardiac GRK2 expression was not altered; however, there was a twofold increase in GRK2 activity during CABG. There was an even greater elevation in cardiac GRK2 activity in patients with severely depressed ventricular function.


CONCLUSIONS
Increased myocardial GRK2 activity appears to be the primary mechanism of impaired beta-AR signaling during CABG with CPB and cardioplegic arrest. This may contribute to the greater need for inotropic support in patients with severe ventricular dysfunction. Strategies to inhibit activation of GRK2 during CABG may decrease morbidity in this patient population.
Bulcao
Christian F
CF
Department of Surgery, Section of Cardiothoracic Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Pandalai
Prakash K
PK
D'Souza
Karen M
KM
Merrill
Walter H
WH
Akhter
Shahab A
SA
D000368:Aged; D000704:Analysis of Variance; D015415:Biomarkers / Q000378:metabolism; D002315:Cardiopulmonary Bypass / Q000009:adverse effects* / Q000379:methods; D015331:Cohort Studies; D001026:Coronary Artery Bypass / Q000009:adverse effects / Q000379:methods*; D003327:Coronary Disease / Q000401:mortality / Q000473:pathology / Q000601:surgery; D017558:Elective Surgical Procedures; D005260:Female; D005500:Follow-Up Studies; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D006324:Heart Arrest, Induced / Q000009:adverse effects* / Q000379:methods; D006801:Humans; D015151:Immunoblotting; D007431:Intraoperative Complications / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D011182:Postoperative Care; D011300:Preoperative Care; D011336:Probability; D018343:Receptors, Adrenergic, beta-2 / Q000032:analysis / Q000378:metabolism*; D012680:Sensitivity and Specificity; D015398:Signal Transduction; D015996:Survival Rate; D016896:Treatment Outcome
D015415:Biomarkers; D018343:Receptors, Adrenergic, beta-2; D054769:G-Protein-Coupled Receptor Kinase 2