Targeting miR-423-5p Reverses Exercise Training-Induced HCN4 Channel Remodeling and Sinus Bradycardia.
Targeting miR-423-5p Reverses Exercise Training-Induced HCN4 Channel Remodeling and Sinus Bradycardia.
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DOI：
10.1161/circresaha.117.311607
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发表时间：
2017-10-13
影响因子：
20.1
通讯作者：
Boyett MR
中科院分区：
文献类型：
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作者：
D'Souza A;Pearman CM;Wang Y;Nakao S;Logantha SJRJ;Cox C;Bennett H;Zhang Y;Johnsen AB;Linscheid N;Poulsen PC;Elliott J;Coulson J;McPhee J;Robertson A;da Costa Martins PA;Kitmitto A;Wisløff U;Cartwright EJ;Monfredi O;Lundby A;Dobrzynski H;Oceandy D;Morris GM;Boyett MR
补充数字内容可在文本中找到。起搏离子通道HCN 4（超极化激活的环核苷酸门控通道4）和相应的离子电流If的下调是啮齿动物运动训练诱导的窦性心动过缓的基础。如果这种情况发生在人类身上，它可以解释老年运动员缓慢性心律失常的发病率增加，了解潜在的过程将是重要的。检测HCN 4在运动员训练诱发的心动过缓中的作用，并研究microRNA（miRs）在HCN 4抑制中的作用。与啮齿类动物一样，人类运动员的固有心率显著低于非运动员，在所有受试者中，HCN选择性阻滞剂伊伐布雷定的心率降低作用与固有心率显著相关，与运动员的HCN抑制一致。下一代测序和定量实时逆转录聚合酶链反应显示，在游泳训练的小鼠的窦房结中miR的重塑。计算预测强调了miR-423- 5 p的突出作用。miR-423- 5 p与HCN 4之间的相互作用通过与前体miR-423- 5 p共转染时HCN 4 3′-非翻译区荧光素酶报告基因活性的剂量依赖性降低得到证实（通过预测识别元件的突变消除）。用抗miR-423 - 5 p敲低miR-423 - 5 p通过拯救HCN 4和If逆转训练诱导的心动过缓。进一步的实验表明，在游泳训练小鼠的窦房结中，miR-423- 5 p（内含子miR）及其宿主基因NSRP 1的上调是由转录因子Nkx 2.5的上调驱动的。HCN重塑可能发生在人类运动员以及啮齿动物模型中。miR-423- 5 p通过靶向HCN 4促进训练诱导的心动过缓这项工作提出了miR控制HCN 4和心率的第一个证据。miR-423- 5 p可能是老年运动员病理性窦房结功能障碍的治疗靶点。
Supplemental Digital Content is available in the text. 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. 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. 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. 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.