Data_Sheet_1_Trimetazidine Attenuates Cardiac Dysfunction in Endotoxemia and Sepsis by Promoting Neutrophil Migration.pdf

Aims: Cardiac dysfunction can be a fatal complication during severe sepsis. The migration of neutrophils is significantly impaired during severe sepsis. We sought to determine the role of trimetazidine (TMZ) in regulation of neutrophil migration to the heart in a mouse model of sepsis and endotoxemia, and to identify the mechanism whereby TMZ confers a survival advantage.Methods and Results: C57/BL6 mice were (1) injected with LPS followed by 24-h TMZ administration, or (2) treated with TMZ (20 mg/kg/day) for 1 week post cecal ligation and puncture (CLP) operation. Echocardiography and Millar system detection showed that TMZ alleviated cardiac dysfunction and histological staining showed the failure of neutrophils migration to heart in both LPS- and CLP-induced mice. Bone marrow transplantation revealed that TMZ-pretreated bone marrow cells improved LPS- and CLP-induced myocardial dysfunction and enhanced neutrophil recruitment in heart. In CXCL2-mediated chemotaxis assays, TMZ increased neutrophils migration via AMPK/Nrf2-dependent up-regulation of CXCR2 and inhibition of GRK2. Furthermore, using luciferase reporter gene and chromatin immunoprecipitation assays, we found that TMZ promoted the binding of the Nrf2 and CXCR2 promoter regions directly. Application of CXCR2 inhibitor completely reversed the protective effects of TMZ in vivo. Co-culture of neutrophils and cardiomyocytes further validated that TMZ decreased LPS-induced cardiomyocyte pyroptosis by targeting neutrophils.Conclusion: Our findings suggested TMZ as a potential therapeutic agent for septic or endotoxemia associated cardiac dysfunction in mice.STUDY HIGHLIGHTS What is the current knowledge on the topic?Migration of neutrophils is significantly impaired during severe sepsis, but the underlying mechanisms remain unknown.What question did this study address?The effects of TMZ on cardiac dysfunction via neutrophils migration.What this study adds to our knowledgeTMZ attenuated LPS-induced cardiomyocyte pyroptosis and cardiac dysfunction by promoting neutrophils recruitment to the heart tissues via CXCR2.How this might change clinical pharmacology or translational scienceOur findings suggested TMZ as a potential therapeutic agent for septic cardiac dysfunction.

目的：心脏功能障碍可能是重症脓毒症期间致命的并发症。在重症脓毒症期间，中性粒细胞的迁移显著受损。本研究旨在探讨三甲氧基苯甲酰胺（TMZ）在调节脓毒症和内毒素血症小鼠模型中中性粒细胞向心脏迁移中的作用，以及确定TMZ赋予生存优势的机制。方法与结果：对C57/BL6小鼠进行（1）脂多糖（LPS）注射后，随后进行24小时的TMZ给药，或（2）在盲肠结扎穿孔（CLP）手术后的第1周内给予TMZ（20 mg/kg/天）治疗。超声心动图和Millar系统检测显示，TMZ缓解了心脏功能障碍，组织学染色显示LPS和CLP诱导的小鼠中性粒细胞向心脏迁移失败。骨髓移植表明，TMZ预处理骨髓细胞改善了LPS和CLP诱导的心肌功能障碍，并增强了心脏中的中性粒细胞募集。在CXCL2介导的趋化实验中，TMZ通过AMPK/Nrf2依赖性上调CXCR2和抑制GRK2，增加了中性粒细胞的迁移。此外，使用荧光素酶报告基因和染色质免疫沉淀实验，我们发现TMZ直接促进了Nrf2和CXCR2启动子区域的结合。应用CXCR2抑制剂完全逆转了TMZ在体内的保护作用。中性粒细胞和心肌细胞的共培养进一步证实了TMZ通过靶向中性粒细胞降低了LPS诱导的心肌细胞焦亡。结论：我们的研究结果提示，TMZ可作为治疗小鼠脓毒症或内毒素血症相关心脏功能障碍的潜在治疗药物。研究亮点：目前对该主题的了解如何？在重症脓毒症期间，中性粒细胞的迁移显著受损，但其潜在机制尚不清楚。本研究旨在解决什么问题？TMZ通过中性粒细胞迁移对心脏功能障碍的影响。本研究对我们知识的贡献是什么？TMZ通过促进中性粒细胞向心脏组织募集，通过CXCR2减弱了LPS诱导的心肌细胞焦亡和心脏功能障碍。这如何改变临床药理学或转化科学？我们的研究结果提示，TMZ可作为治疗脓毒症心脏功能障碍的潜在治疗药物。