Targeting miR-423-5p reverses exercise training–induced HCN4 channel remodeling and sinus bradycardia

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D’Souza, A, Pearman, CM, Wang, Y, Nakao, S, Logantha, SJR, Cox, C, Bennett, H, Zhang, Y, Johnsen, AB, Linscheid, N, Poulsen, PC, Elliott, J, Coulson, J ORCID: https://orcid.org/0000-0001-9758-6295, McPhee, J, Robertson, A, Da Costa Martins, PA, Kitmitto, A, Wisløff, U, Cartwright, EJ, Monfredi, O, Lundby, A, Dobrzynski, H, Oceandy, D, Morris, GM and Boyett, MR, 2017. Targeting miR-423-5p reverses exercise training–induced HCN4 channel remodeling and sinus bradycardia. Circulation Research, 121 (9), pp. 1058-1068. ISSN 0009-7330

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Official URL: http://doi.org/10.1161/circresaha.117.311607

Abstract

Rationale: Downregulation of the pacemaking ion channel, HCN4 (hyperpolarization-activated cyclic nucleotide gated channel 4), and the corresponding ionic current, If, underlies exercise training–induced sinus bradycardia in 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 bradycardia in 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 miRs in 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 bradycardia via rescue of HCN4 and If. 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 bradycardia by targeting HCN4. This work presents the first evidence of miR control of HCN4 and heart rate. miR-423-5p could be a therapeutic target for pathological sinus node dysfunction in veteran athletes.

Item Type:	Journal article
Publication Title:	Circulation Research
Creators:	D’Souza, A., Pearman, C.M., Wang, Y., Nakao, S., Logantha, S.J.R., Cox, C., Bennett, H., Zhang, Y., Johnsen, A.B., Linscheid, N., Poulsen, P.C., Elliott, J., Coulson, J., McPhee, J., Robertson, A., Da Costa Martins, P.A., Kitmitto, A., Wisløff, U., Cartwright, E.J., Monfredi, O., Lundby, A., Dobrzynski, H., Oceandy, D., Morris, G.M. and Boyett, M.R.
Publisher:	Lippincott Williams & Wilkins
Date:	October 2017
Volume:	121
Number:	9
ISSN:	0009-7330
Identifiers:	Number Type 10.1161/circresaha.117.311607 DOI
Rights:	© 2017 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
Divisions:	Schools > School of Science and Technology
Record created by:	Linda Sullivan
Date Added:	29 Jun 2018 09:51
Last Modified:	29 Jun 2018 09:51
URI:	https://irep.ntu.ac.uk/id/eprint/33952