Uncoupling of Myocardial β-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 β-adrenergic receptors (β-ARs). Impaired signaling through this pathway can have a detrimental effect on ventricular function and increased need for inotropic support. The mechanism of myocardial β-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 β-ARs, as a primary mechanism of β-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 β-AR signaling was assessed by measuring total β-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 β-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 β-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.