Department of Anesthesiology and Pain Medicine, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8602, Japan.
Department of Molecular Medicine and Anatomy, Graduate School of Medicine, Nippon Medical School, Tokyo 113-8602, Japan.
Int J Mol Med. 2014 Jul;34(1):291-8. doi: 10.3892/ijmm.2014.1739. Epub 2014 Apr 9.
The volatile anesthetic, sevoflurane, is widely used in surgery. Over the years, there has been a growing interest in the biological effects of sevoflurane on tissue and organ systems and the molecular mechanisms involved. MicroRNAs (miRNAs or miRs) acting as pivotal post‑transcriptional regulators for fine-tuning gene networks are not only expressed intracellularly, but are also secreted into the plasma. However, the sevoflurane‑associated dynamics of circulating miRNAs and the effects of sevoflurane on tissues remain unknown. Thus, the aim of this study was to perform a comprehensive analysis of circulating miRNA levels and compositions in sevoflurane‑anesthetized rats. The rats were allowed to breathe spontaneously under 2% sevoflurane anesthesia for 6 h, and we performed a quantitative polymerase chain reaction (PCR)‑based array analysis of the time-dependent changes in plasma miRNA levels and compositions. Subsequently, we validated the levels of muscle‑specific miRNAs (also known as myomiRNAs; miR-1, miR‑133a, miR-133b and miR-206) of the plasma, heart and skeletal muscle by quantitative PCR following 3 and 6 h of anesthesia, as well as at 1, 3, 7 and 14 days post-anesthesia. Of the 210 miRNAs detected in the rat plasma from the control group (no anesthesia), 161 plasma miRNAs (77%) were transiently downregulated as a result of sevoflurane anesthesia. Although the downregulation of the plasma miRNAs (148 out of the 161 plasma mRNAs; 92%) recovered immediately after anesthesia, the plasma levels of 4 muscle-specific miRNAs were persistently downregulated until 14 days post-anesthesia. In the cardiac and skeletal muscles, the expression levels of the muscle-specific miRNAs were upregulated within 2 weeks post-anesthesia, indicating that the expression levels of the muscle-specific miRNAs in the cardiac and skeletal muscles and their plasma levels are substantially inversely correlated following anesthesia. Our data suggest that sevoflurane predominantly affects cardiac and skeletal muscles and suppresses the release of miRNA from these tissues into the circulation. This new information provides novel insight into the molecular mechanisms of action of the anesthetic, sevoflurane.
挥发性麻醉剂七氟醚广泛应用于外科手术。多年来，人们对七氟醚对组织和器官系统的生物学效应以及涉及的分子机制越来越感兴趣。微 RNA（miRNA 或 miR）作为精细调节基因网络的关键转录后调节剂，不仅在细胞内表达，而且还分泌到血浆中。然而，七氟醚相关的循环 miRNA 动态变化以及七氟醚对组织的影响尚不清楚。因此，本研究旨在全面分析七氟醚麻醉大鼠的循环 miRNA 水平和组成。大鼠在 2%七氟醚麻醉下自主呼吸 6 小时，我们进行了基于定量聚合酶链反应（PCR）的阵列分析，以研究血浆 miRNA 水平和组成的时间依赖性变化。随后，我们通过定量 PCR 验证了血浆、心脏和骨骼肌中的肌肉特异性 miRNA（也称为肌源性 miRNA；miR-1、miR-133a、miR-133b 和 miR-206）水平，麻醉后 3 小时和 6 小时以及麻醉后 1、3、7 和 14 天。在对照组（无麻醉）大鼠血浆中检测到的 210 个 miRNA 中，161 个血浆 miRNA（77%）因七氟醚麻醉而短暂下调。尽管麻醉后这些血浆 miRNA（161 个血浆 miRNA 中的 148 个；92%）立即恢复下调，但 4 种肌肉特异性 miRNA 的血浆水平直到麻醉后 14 天仍持续下调。在心脏和骨骼肌中，肌肉特异性 miRNA 的表达水平在麻醉后 2 周内上调，表明麻醉后心脏和骨骼肌中肌肉特异性 miRNA 的表达水平及其血浆水平与麻醉后显著呈负相关。我们的数据表明，七氟醚主要影响心脏和骨骼肌，并抑制这些组织中 miRNA 的释放到循环中。这些新信息为麻醉剂七氟醚的作用机制提供了新的见解。
