【罂粟摘要】运动训练揭示微小RNA与改善心肌梗死后心力衰竭大鼠的心功能和电生理相关
运动训练揭示微小RNA与改善心肌梗死后心力衰竭大鼠的心功能和电生理相关
目的：耐力训练改善心力衰竭患者的有氧能力和心功能。然而，潜在的机制还没有得到很好的描述。因此，运动训练可以作为一种工具来发现心衰治疗的新靶点。我们的目的是将运动训练心力衰竭大鼠钙处理和电生理的改变与microRNA(MiRNA)谱相关联，以确定哪些miRNA在钙处理和电生理中引起类似心衰的效应。
方法：建立SD大鼠心肌梗死后心力衰竭模型。所有心肌梗死面积>40%的心衰大鼠左心室（LV）被选作全心脏实验，细胞实验或分子分析; 通过超声心动图检查（Vevo 770，视觉系统，加拿大多伦多）在1.5%异氟烷和40%氧气60%中进行在左胸骨旁位置用一个24兆赫换能器的N2O麻醉混合物。射血分数（EF）和缩短分数（FS）用光标根据M型腔尺寸,计算垂直于左室前后壁放置。心肌梗死大鼠随机分为安静对照组(Sed)、中等强度耐力训练组(MOD)和高强度耐力训练组(Mod)，训练时间为8 周。运动训练:大鼠在代谢室的定制跑步机上跑步，高强度运动训练为上坡跑（25°），在VO2max的85%-90%下4分钟和50%的VO2max2分钟，60分钟/天，5天/周， 8周。这个中等强度运动训练大鼠交替上上坡跑（25°）在最大摄氧量为65–70%时为4分钟，在最大摄氧量为50%时为2分钟, 60分钟/天，5天/周， 8周。
结果：运动训练改善了心脏功能、钙处理和电生理学，包括以一种运动强度依赖的方式降低对心律失常的易感性，而高强度的运动效果更大。55个miRNAs在MI-sed中被显著上调或下调，其中18个和3个在MI-HIGH和MI-MOD中分别向Sham-sed转变。此后，我们在实验上改变了这些“运动miRNAs”在人类诱导多能干细胞来源的心肌细胞(hiPSC-CM)中的表达，方向与它们在心肌梗死中的变化方向相同。在“运动-miRNAs”中，miR-214-3p延长AP时程，而miR-140和miR-208A则缩短AP时程。MiR-497-5P延缓Ca2+释放，miR-214-3P和miR-31a-5P延缓Ca2+衰变。
结论：以运动训练为工具，我们发现miR-214-3p、miR-497-5p、miR-31a-5p在钙处理和电生理方面与心力衰竭的行为有关，有可能成为潜在的治疗靶点。
Exercise training reveals micro-RNAs associated with improved cardiac function and electrophysiology in rats with heart failure after myocardial infarction
Aims: Endurance training improves aerobic ftness and cardiac function in individuals with heart failure. However, the underlying mechanisms are not well characterized. Exercise training could therefore act as a toolto discover novel targets for heart failure treatment. We aimed to associate changes in Ca2+ handling andelectrophysiology with micro-RNA (miRNA) profle in exercise trained heart failure rats to establish whichmiRNAs induce heart failure-like effects in Ca2+ handling and electrophysiology.
Methods and results: Post-myocardial infarction (MI) heart failure was induced in Sprague Dawley rats. Rats withMI were randomized to sedentary control (sed), moderate (mod)- or high-intensity (high) endurance training for8 weeks. Exercise training improved cardiac function, Ca2+ handling and electrophysiology including reducedsusceptibility to arrhythmia in an exercise intensity-dependent manner where high intensity gave a larger effect.Fifty-fve miRNAs were signifcantly regulated (up or down) in MI-sed, of which 18 and 3 were changed towards Sham-sed in MI-high and MI-mod, respectively. Thereafter we experimentally altered expression of these “exercise-miRNAs” individually in human induced pluripotent stem cell-derived cardiomyocytes (hIPSC-CM) in the same direction as they were changed in MI. Of the “exercise-miRNAs”, miR-214-3p prolonged AP duration,whereas miR-140 and miR-208a shortened AP duration. miR-497-5p prolonged Ca2+ release whereas miR-214-
3p and miR-31a-5p prolonged Ca2+ decay.
Conclusion: Using exercise training as a tool, we discovered that miR-214-3p, miR-497-5p, miR-31a-5p contribute to heart-failure like behaviour in Ca2+ handling and electrophysiology and could be potential treatment targets.
翻译：安丽 编辑：佟睿 审校：曹莹