Sevoflurane anesthesia persistently downregulates muscle-specific microRNAs in rat plasma

Abstract

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.