Targeting miR-423-5p Reverses Exercise Training–Induced HCN4 Channel Remodeling and Sinus Bradycardia
2017
Rationale: Downregulation of the pacemaking ion channel, HCN4 (hyperpolarization-activated cyclic nucleotide gated channel 4), and the corresponding ionic current, I f , underlies exercise training–induced
sinus bradycardiain rodents. If this occurs in humans, it could explain the increased incidence of bradyarrhythmias in veteran athletes, and it will be important to understand the underlying processes. Objective: To test the role of HCN4 in the training-induced
bradycardiain human athletes and investigate the role of microRNAs (
miRs) in the repression of HCN4. Methods and Results: As in rodents, the intrinsic heart rate was significantly lower in human athletes than in nonathletes, and in all subjects, the rate-lowering effect of the HCN selective blocker,
ivabradine, was significantly correlated with the intrinsic heart rate, consistent with HCN repression in athletes. Next-generation sequencing and quantitative real-time reverse transcription polymerase chain reaction showed remodeling of
miRsin the sinus node of swim-trained mice. Computational predictions highlighted a prominent role for
miR-423-5p. Interaction between
miR-423-5p and HCN4 was confirmed by a dose-dependent reduction in HCN4 3′-untranslated region luciferase reporter activity on cotransfection with precursor
miR-423-5p (abolished by mutation of predicted recognition elements). Knockdown of
miR-423-5p with anti-
miR-423-5p reversed training-induced
bradycardiavia rescue of HCN4 and I f . Further experiments showed that in the sinus node of swim-trained mice, upregulation of
miR-423-5p (intronic
miR) and its host gene, NSRP1, is driven by an upregulation of the transcription factor Nkx2.5. Conclusions: HCN remodeling likely occurs in human athletes, as well as in rodent models.
miR-423-5p contributes to training-induced
bradycardiaby targeting HCN4. This work presents the first evidence of
miRcontrol of HCN4 and heart rate.
miR-423-5p could be a therapeutic target for pathological sinus node dysfunction in veteran athletes.
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