Circadian rhythms influence the incidence of sudden cardiac death after chronic heart failure (CHF) but the underlying mechanisms are not well defined. We sought to investigate the role of the β-adrenergic receptor (β-AR) in cardiac circadian disorders and ventricular arrhythmia(VA) after CHF. CHF guinea pigs was created by transverse aorta constriction. Circadian variations of the myocardial expressions ofβ1-AR, β2-AR and circadian genes CLOCK and BMAL1 were examined by real time reverse transcription polymerase chain reaction, Western blot and immunohistochemistry. Sham operated animals showed circadian oscillations in the expression ofβ1-AR and CLOCK-BMAL1(P<0.05). However, the expression ofβ1-AR and CLOCK-BMAL1 were attenuated in guinea pigs with CHF(P<0.05). Then, electrocardiograms of Langendorff-perfused hearts with isoprenaline(β-AR nonselective agonist ,ISO), ISO + CGP-20712A(β1-AR selective antagonist, CGP) and ISO + ICI118551(β2-AR selective antagonist, ICI) at CT3 and CT15 were recorded and ventricular arrhythmias were induced by programmed electrical stimulation (PES). During ISO and ISO + ICI infusion, the diurnal variation in response of β-AR activation translated to a greater incidence of VA in CT15(P<0.05). Next, infections of Ad-CLOCK and/or Ad-BMAL1 were applied to overexpress CLOCK, BMAL1 and CLOCK-BMAL1 in the guinea pig ventricular cardiomyocytes. Ad-CLOCK and Ad-BMAL1 co-infection resulted in overexpression of β1-AR and a greater incidence of arrhythmic activity in myocytes. At last, chromatin immunoprecipitation assay(ChIP) and luciferase(LUC) were applied to determine whether CLOCK-BMAL1 transcriptionally regulateβ1-AR expression. ChIP-qPCR analysis and luciferase revealed that BMAL1 could bind to enhancer of β1-AR to regulate arrhythmia severity after CHF(P<0.05). We conclude that circadian rhythms of myocardial β1-AR and CLOCK-BMAL1 activities are disturbed after CHF. Attenuation of CLOCK-BMAL1 transcriptionally decreases the expression of β1-AR to anticipate the occurrence of ventricular arrhythmias after CHF.
Jiamin, Y., Qian, Z., Ge, P., Wang, Y., Chen, Y., Hou, X., & Zou, J. (2014). GW25-e0796 Attenuation of CLOCK-BMAL1 transcriptionally decreases the expression of β1-AR to anticipate the occurrence of ventricular arrhythmia after chronic heart failure. Journal of the American College of Cardiology, 64(16), C75. https://doi.org/10.1016/j.jacc.2014.06.349