Abstract
A decrease in the rapid component of delayed rectifier potassium current (IKr) during chronic heart failure (CHF) prolongs action potential (AP), and plays a key rolein the pathogenesis of ventricular arrhythmias. β-Arrestin2 has been shown to restore the inotropic reserve of β-adrenergic regulation, but little or nothing is known about its effect on intrinsic channel. This study investigated the role of β-arrestin2 in the regulation of cardiac hERG/IKr potassium channel and AP during chronic adrenergic stimulation. Single left ventricular myocytes were isolated from guinea pig heart, and were transfected with adenovirus encoding β-arrestin2, or β-arrestin2 siRNA or an empty adenovirus. Cell cultures containing 10 nM isoproterenol, 1 nM phenylephrine or vehicle alone (control medium) were electro-physiologically examined after 48 h of incubation. Action potential duration at 50 and 90 % of repolarization (APD50 and APD90) were measured using whole-cell patch-clamp recording. Sustained adrenergic stimulation significantly reduced the density of the IKr current (p < 0.001). β-Arrestin2 expression in cell cultures treated with isoproterenol or phenylephrine was significantly downregulated after adrenergic stimulation (p < 0.001). Overexpression of β-arrestin2 significantly attenuated isoproterenol or phenylephrine-induced reduction in IKr current. It also prevented the phenylephrine-induced prolongation of AP (p < 0.05 for APD50 and p < 0.001 for APD90), but did not significantly affect AP profile after exposure of the cardiomyocytes to isoproterenol (p > 0.05). Therefore, Increased levels of β-Arrestin2 weaken dysregulation of IKr current and prevent excessive AP prolongation, making it an effective anti-arrhythmic strategy.
Highlights
Introduction adrenergic stimulationVentricular arrhythmias are a common cause of sudden cardiac death among patients with chronic heart failure(CHF)
A decrease in the rapid component of delayed rectifier potassium current (IKr) during chronic heart failure (CHF) prolongs action potential (AP), and plays a key role in the pathogenesis of ventricular arrhythmias. β-Arrestin2 has been shown to restore the inotropic reserve of β-adrenergic regulation, but little or nothing is known about its effect on intrinsic channel
This study investigated the role of β-arrestin2 in the regulation of cardiac human ether-a-go-go-related gene (hERG)/IKr potassium channel and AP during chronic adrenergic stimulation
Summary
Introduction adrenergic stimulationVentricular arrhythmias are a common cause of sudden cardiac death among patients with chronic heart failure(CHF). Rapid component of delayed rectifier potassium channel (IKr) is encoded by the human ether-a-go-go-related gene (hERG), and is most responsible for phase 3 repolarization [4, 5]. Neural routes and humoral factors have been used to study IKr. Activation of β1-adrenergic receptor (ADRB1) results in the activation of adenylate cyclase which in turn catalyzes the conversion of ATP to cyclic AMP (cAMP), thereby increasing the intracellular concentration of the second messenger. It has been reported that β-arrestin may play a cardioprotective role in CHF [9,10,11]. A β-arrestin-mediated increase in IKr has been reported in hERG-HEK cells [12]. This study investigated the role of β-arrestin in the regulation of cardiac hERG/IKr potassium channel and AP during chronic
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