miR-423-5p靶向治疗可逆转运动训练诱发的HCN4通道重构和窦性心动过缓
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Targeting miR-423-5p Reverses Exercise Training–Induced HCN4 Channel Remodeling and Sinus Bradycardia
背景与目的
抑制起搏离子通道，HCN 4(超极化激活的环核苷酸门控通道4)，以及相应的离子电流，If作为运动诱发的窦性心动过缓的基础。如果这发生在人类身上，它可以解释老兵运动员缓慢性心律失常发生率的增加，了解潜在的过程是很重要的。目的：检测HCN4在运动员训练性心动过缓中的作用，探讨microRNAs (miRs) 在HCN4抑制中的作用。
方 法
与啮齿动物一样，人类运动员的固有心率明显低于非运动员，在所有受试者中，HCN选择性阻滞剂伊夫巴定的速率降低效应与固有心率显著相关，与运动训练小鼠的HCN抑制相一致。下一代测序和定量实时逆转录聚合酶链反应显示游泳训练小鼠窦房结的心肌重塑。
结 果
计算预测结果表明，mir-423-5p与HCN4之间的相互作用具有显著的作用。HCN4 4 3'-非翻译区荧光素酶报告活性与前体mir-423-5p共转染(通过预测识别元件的突变而消失)，证实了它们之间的相互作用。用反mir-423-5p沉默mir-423-5p通过HCN4和If的救援逆转训练所致的心动过缓。进一步的实验表明，在游泳训练小鼠的窦房结中，上调mir-423-5p(内含miR)及其宿主基因nsrp 1是由转录因子NKX 2.5的上调所致。
结 论
HCN重塑可能发生在人类运动员和啮齿类动物模型中。mir-423-5p通过HCN4靶向作用参与训练所致的心动过缓。本研究首次证明miR对hCN4和心率的控制。miR-423-5p可作为老年运动员病理性窦房结功能障碍的治疗靶点。
原始文献摘要
D'Souza A, Pearman CM, Wang Y, et al. Targeting miR-423-5p Reverses Exercise Training-Induced HCN4 Channel Remodeling and Sinus Bradycardia. Circ Res. 2017 Oct 13;121(9):1058-1068. doi: 10.1161/CIRCRESAHA.117.311607. Epub 2017 Aug 17.
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.
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