Abstract
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.
Published Version
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