Shi Jian, Chen Yuhong, Zhi Haijun, An Hui, Hu Zhenjie
Department of Intensive Care Unit, Hebei Medical University Fourth Affiliated Hospital and Hebei Provincial Tumor Hospital, Shijiazhuang, China.
Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Shijiazhuang, China.
Ann Transl Med. 2022 Feb;10(4):212. doi: 10.21037/atm-22-483.
Sepsis is a leading cause of death in China, the mortality rate of which is elevated when cardiac dysfunction is induced. Levosimendan is used for the treatment of decompensated cardiac failure. In this study, we sought to investigate the role of levosimendan in the inflammation, oxidative stress, and mitophagic response of the septic heart.
A lipopolysaccharide (LPS)-induced septic myocardial dysfunction mouse model was established. To study the relationship between levosimendan and inflammation, oxidative stress, and mitophagy response, mice were pretreated with mdivi-1 (an inhibitor of mitophagy) prior to LPS administration. Levosimendan was given (24 µg/kg) via intraperitoneal injection 3 h after LPS had been administered. At 6 h after LPS injection, echocardiographic analysis, enzyme-linked immunosorbent assay (ELISA), oxidative stress index, myocardial pathological changes, transmission electron microscopy (TEM), immunofluorescence, and western blot were used to investigate the protective effects of levosimendan against LPS-induced myocardial dysfunction.
In the sepsis model, levosimendan markedly ameliorated myocardial dysfunction, decreased the release of myocardial enzymes and inflammatory cytokines, improved oxidative stress index and myocardial pathological changes, reduced mitochondrial division, and activated mitophagy. To confirm whether the protection of levosimendan was mediated by mitophagy, a mitophagy inhibitor-mdivi-1 was used in this study. It significantly impaired the protective effects of levosimendan. In addition, our studies further confirmed the protection of levosimendan against LPS-induced myocardial injury and the mechanisms involving PINK-1-Parkin mediated mitophagy signaling.
Levosimendan was able to rescue the LPS-induced cardiac dysfunction mice, supporting its mechanism of action by suppressing inflammation, oxidative stress, and directly targeting the PINK-1-Parkin pathway.
脓毒症是中国主要的死亡原因之一，当诱发心脏功能障碍时其死亡率会升高。左西孟旦用于治疗失代偿性心力衰竭。在本研究中，我们旨在探究左西孟旦在脓毒症心脏的炎症、氧化应激和线粒体自噬反应中的作用。
建立脂多糖（LPS）诱导的脓毒症心肌功能障碍小鼠模型。为研究左西孟旦与炎症、氧化应激和线粒体自噬反应之间的关系，在给予LPS之前用mdivi-1（一种线粒体自噬抑制剂）对小鼠进行预处理。在给予LPS 3小时后通过腹腔注射给予左西孟旦（24μg/kg）。在注射LPS后6小时，使用超声心动图分析、酶联免疫吸附测定（ELISA）、氧化应激指标、心肌病理变化、透射电子显微镜（TEM）、免疫荧光和蛋白质印迹法来研究左西孟旦对LPS诱导的心肌功能障碍的保护作用。
在脓毒症模型中，左西孟旦显著改善心肌功能障碍，降低心肌酶和炎性细胞因子的释放，改善氧化应激指标和心肌病理变化，减少线粒体分裂，并激活线粒体自噬。为了确认左西孟旦的保护作用是否由线粒体自噬介导，本研究使用了线粒体自噬抑制剂mdivi-1。它显著削弱了左西孟旦的保护作用。此外，我们的研究进一步证实了左西孟旦对LPS诱导的心肌损伤的保护作用以及涉及PINK-1-Parkin介导的线粒体自噬信号传导的机制。
左西孟旦能够挽救LPS诱导的心脏功能障碍小鼠，支持其通过抑制炎症、氧化应激并直接靶向PINK-1-Parkin途径的作用机制。
