Exercise training reveals micro-RNAs associated with improved cardiac function and electrophysiology in rats with heart failure after myocardial infarction.,Journal of Molecular and Cellular Cardiology

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Exercise training reveals micro-RNAs associated with improved cardiac function and electrophysiology in rats with heart failure after myocardial infarction.
Journal of Molecular and Cellular Cardiology ( IF 4.9 ) Pub Date : 2020-09-10 , DOI: 10.1016/j.yjmcc.2020.08.015
Tomas O Stølen ₁ , Morten A Høydal ₁ , Muhammad Shakil Ahmed ₂ , Kari Jørgensen ₃ , Karin Garten ₃ , Maria P Hortigon-Vinagre ₄ , Victor Zamora ₄ , Nathan R Scrimgeour ₃ , Anne Marie Ormbostad Berre ₃ , Bjarne M Nes ₅ , Eirik Skogvoll ₆ , Anne Berit Johnsen ₃ , Jose B N Moreira ₃ , Julie R McMullen ₇ , Håvard Attramadal ₂ , Godfrey L Smith ₈ , Øyvind Ellingsen ₅ , Ulrik Wisløff ₉

Affiliation

Department of Circulation and Medical Imaging, Faculty of Medicine and Health, Norwegian University of Science and Technology, Trondheim, Norway; Department of Cardiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway; Department of Cardiothoracic Surgery, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
Institute for Surgical Research, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
Department of Circulation and Medical Imaging, Faculty of Medicine and Health, Norwegian University of Science and Technology, Trondheim, Norway.
Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Science, University of Glasgow 126 University Place, Glasgow G12 8TA, United Kingdom.
Department of Circulation and Medical Imaging, Faculty of Medicine and Health, Norwegian University of Science and Technology, Trondheim, Norway; Department of Cardiology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
Department of Circulation and Medical Imaging, Faculty of Medicine and Health, Norwegian University of Science and Technology, Trondheim, Norway; Department of Anesthesia and Intensive Care Medicine, St. Olav University Hospital, Trondheim, Norway.
Cardiac Hypertrophy Laboratory, Baker Heart & Diabetes Institute, 75 Commercial Road, Melbourne, VIC, Australia.
Department of Circulation and Medical Imaging, Faculty of Medicine and Health, Norwegian University of Science and Technology, Trondheim, Norway; Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Science, University of Glasgow 126 University Place, Glasgow G12 8TA, United Kingdom.
Department of Circulation and Medical Imaging, Faculty of Medicine and Health, Norwegian University of Science and Technology, Trondheim, Norway; School of Human Movement & Nutrition Sciences, University of Queensland, Australia.

Aims

Endurance training improves aerobic fitness and cardiac function in individuals with heart failure. However, the underlying mechanisms are not well characterized. Exercise training could therefore act as a tool to discover novel targets for heart failure treatment. We aimed to associate changes in Ca²⁺ handling and electrophysiology with micro-RNA (miRNA) profile in exercise trained heart failure rats to establish which miRNAs 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 with MI were randomized to sedentary control (sed), moderate (mod)- or high-intensity (high) endurance training for 8 weeks. Exercise training improved cardiac function, Ca²⁺ handling and electrophysiology including reduced susceptibility to arrhythmia in an exercise intensity-dependent manner where high intensity gave a larger effect. Fifty-five miRNAs were significantly 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.

中文翻译：

运动训练揭示了与心肌梗塞后心力衰竭大鼠心脏功能和电生理改善相关的微 RNA。

宗旨

耐力训练可改善心力衰竭患者的有氧健康和心脏功能。然而，潜在的机制没有得到很好的表征。因此，运动训练可以作为发现心力衰竭治疗新目标的工具。我们旨在将 Ca ²⁺处理和电生理学的变化与经过运动训练的心力衰竭大鼠的 micro-RNA (miRNA) 谱相关联，以确定哪些 miRNA 在 Ca ²⁺处理和电生理学中诱导心力衰竭样效应。

方法和结果

在 Sprague Dawley 大鼠中诱发了心肌梗塞后 (MI) 心力衰竭。MI 大鼠随机接受久坐控制 (sed)、中等 (mod) 或高强度 (high) 耐力训练 8 周。运动训练改善心脏功能，Ca ²⁺处理和电生理学包括以运动强度依赖的方式降低对心律失常的敏感性，其中高强度产生更大的影响。55 个 miRNA 在 MI-sed 中被显着调节（上调或下调），其中 18 个和 3 个在 MI-high 和 MI-mod 中分别向 Sham-sed 变化。此后，我们实验性地改变了这些“运动-miRNA”在人诱导多能干细胞衍生心肌细胞（hIPSC-CM）中的表达，其表达方向与它们在 MI 中的变化方向相同。在“运动-miRNA”中，miR-214-3p 延长了 AP 持续时间，而 miR-140 和 miR-208a 缩短了 AP 持续时间。miR-497-5p 延长 Ca ²⁺释放，而 miR-214-3p 和 miR-31a-5p 延长 Ca ²⁺衰变。