Levosimendan protects from sepsis-inducing cardiac dysfunction by suppressing inflammation, oxidative stress and regulating cardiac mitophagy via the PINK-1-Parkin pathway in mice

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.