Sepsis-induced cardiomyopathy (SICM) is common complication in septic patients with a high mortality and is characterized by an abnormal inflammation response, which was precisely regulated by endogenous specialized pro-resolving mediators (SPMs). However, the metabolic changes of cardiac SPMs during SICM and the roles of SPMs subset in the development of SICM remain unknown. In this work, the SPMs concentration was assessed using ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) of SICM mice and SICM patients. The cardiac function was measured by echocardiography after the treatment of a SPMs subset, termed Resolvin D2 (RvD2). Caspase-11, GSDMD and double deficient (Caspase-11GSDMD) mice were used to clarify the mechanisms of RvD2 in SICM. We found that endogenous cardiac SPMs were disorders and RvD2 was decreased significantly and correlated with left ventricular ejection fraction (LVEF) and β-BNP, cTnT in Lipopolysaccharide/Cecum ligation and puncture (CLP) induced SICM models. Treatment with RvD2 attenuated lethality, cardiac dysfunction and cardiomyocytes death during SICM. Mechanistically, RvD2 alleviated SICM via inhibiting Caspase-11/GSDMD-mediated cardiomyocytes pyroptosis. Finally, the plasma levels of RvD2 were also decreased and significantly correlated with IL-1β, β-BNP, cTnT and LVEF in patients with SICM. Of note, plasma RvD2 level is indicator of SICM patients from healthy controls or sepsis patients. These findings suggest that decreased cardiac RvD2 may involve in the pathogenesis of SICM. In addition, treatment with RvD2 represents a novel therapeutic strategy for SICM by inhibiting cardiomyocytes pyroptosis.

中文翻译：

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Cardiac Resolvin D2 通过抑制 Caspase-11/GSDMD 依赖性焦亡来改善脓毒症诱发的心肌病

脓毒症诱发的心肌病（SICM）是脓毒症患者常见的并发症，死亡率高，其特点是异常的炎症反应，而炎症反应受到内源性专门促消退介质（SPM）的精确调节。然而，SICM期间心脏SPM的代谢变化以及SPM子集在SICM发展中的作用仍不清楚。在这项工作中，使用超高效液相色谱串联质谱 (UPLC-MS/MS) 对 SICM 小鼠和 SICM 患者的 SPM 浓度进行了评估。在 SPM 子集（称为 Resolvin D2 (RvD2)）治疗后，通过超声心动图测量心脏功能。 Caspase-11、GSDMD 和双缺陷 (Caspase-11GSDMD) 小鼠用于阐明 RvD2 在 SICM 中的机制。我们发现在脂多糖/盲肠结扎穿刺（CLP）诱导的SICM模型中，内源性心脏SPM紊乱，RvD2显着降低，并与左心室射血分数（LVEF）和β-BNP、cTnT相关。 RvD2 治疗可减轻 SICM 期间的致死率、心功能障碍和心肌细胞死亡。从机制上讲，RvD2 通过抑制 Caspase-11/GSDMD 介导的心肌细胞焦亡来减轻 SICM。最后，SICM 患者血浆 RvD2 水平也降低，且与 IL-1β、β-BNP、cTnT 和 LVEF 显着相关。值得注意的是，血浆 RvD2 水平是 SICM 患者与健康对照或败血症患者的指标。这些发现表明心脏 RvD2 降低可能参与 SICM 的发病机制。此外，RvD2 治疗代表了一种通过抑制心肌细胞焦亡来治疗 SICM 的新策略。