Myocardial recovery after ischemia and reperfusion injury is significantly impaired in hearts with transgenic overexpression of beta-adrenergic receptor kinase.

BACKGROUND: beta-Adrenergic receptor kinase 1 (beta ARK1) mediates beta-adrenergic receptor signaling via receptor phosphorylation, which results in functional uncoupling. The physiological importance of beta ARK1 on cardiac performance in the setting of ischemia and reperfusion injury, however, has not been clearly established. In this study, the effects of beta ARK1 overexpression on myocardial recovery after ischemia and reperfusion injury were evaluated in transgenic mice with the use of an isolated work-performing murine heart preparation and computerized analysis of functional data. METHODS AND RESULTS: A controlled, experimental study was performed to compare cardiac function in the hearts of both transgenic mice with a 3-fold overexpression of beta ARK1 (n = 6; weight, 25 to 29 g) and littermate controls (n = 9; weight, 25 to 28 g). Preload-dependent cardiac output, contractility, heart rate, stroke work, and stroke volume were evaluated in the 2 groups before and after a 6-minute period of normothermic ischemia. Before ischemia, significant decreases were observed in all parameters of myocardial performance in beta ARK1 mice compared with control mice. After ischemia and reperfusion, significant decreases in cardiac function were observed in both experimental groups; however, significantly lower percentages of myocardial recovery occurred in beta ARK1 hearts compared with control hearts. CONCLUSIONS: After global normothermic ischemia, significant decreases in cardiac function were observed in both beta ARK1 and control mice; however, significantly lower percentages of myocardial recovery occurred in beta ARK1 mice. These data suggest that myocardial beta ARK1 overexpression significantly impairs cardiac function in the setting of ischemia and reperfusion injury.