Trimetazidine Attenuates Cardiac Dysfunction in Endotoxemia and Sepsis by Promoting Neutrophil Migration.
Trimetazidine Attenuates Cardiac Dysfunction in Endotoxemia and Sepsis by Promoting Neutrophil Migration.
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曲美他嗪通过促进中性粒细胞迁移减轻内毒素血症和脓毒症引起的心脏功能障碍
DOI：
10.3389/fimmu.2018.02015
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发表时间：
2018
影响因子：
7.3
通讯作者：
Wang DW
中科院分区：
文献类型：
--
作者：
Chen J;Wang B;Lai J;Braunstein Z;He M;Ruan G;Yin Z;Wang J;Cianflone K;Ning Q;Chen C;Wang DW
目的：心功能不全可能是严重脓毒症的致命并发症。在严重脓毒症期间，中性粒细胞的迁移显著受损。我们试图确定曲美他嗪（TMZ）在调节中性粒细胞迁移到心脏的败血症和内毒素血症的小鼠模型中的作用，并确定TMZ赋予生存优势的机制。方法和结果：C57/BL 6小鼠（1）注射LPS，然后给予TMZ 24小时，或（2）在盲肠结扎和穿刺（CLP）手术后用TMZ（20 mg/kg/天）治疗1周。超声心动图和Millar系统检测显示TMZ减轻了LPS和CLP诱导的小鼠的心功能障碍，组织学染色显示中性粒细胞向心脏迁移失败。骨髓移植显示TMZ预处理的骨髓细胞改善LPS和CLP诱导的心肌功能障碍，并增强心脏中中性粒细胞的募集。在CXCL 2介导的趋化性试验中，TMZ通过AMPK/Nrf 2依赖性上调CXCR 2和抑制GRK 2增加中性粒细胞迁移。此外，使用荧光素酶报告基因和染色质免疫沉淀分析，我们发现TMZ促进Nrf 2和CXCR 2启动子区域的直接结合。应用CXCR 2抑制剂可完全逆转TMZ的保护作用。中性粒细胞和心肌细胞的共培养进一步证实TMZ通过靶向中性粒细胞来减少LPS诱导的心肌细胞焦亡。结论：TMZ对脓毒症或内毒素血症相关的心功能不全有潜在的治疗作用。研究亮点目前对该主题的了解是什么？严重脓毒症时中性粒细胞的迁移显著受损，但其潜在机制尚不清楚。这项研究解决了什么问题？TMZ通过中性粒细胞迁移对心功能不全的影响。这项研究增加了我们的知识TMZ通过促进中性粒细胞通过CXCR 2募集到心脏组织来减轻LPS诱导的心肌细胞焦亡和心功能障碍。这可能会如何改变临床药理学或转化科学我们的研究结果表明TMZ作为一种潜在的治疗药物，脓毒性心功能不全。
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 knowledge TMZ 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 science Our findings suggested TMZ as a potential therapeutic agent for septic cardiac dysfunction.
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影响因子：
5.4
作者：
Makara MA;Hoang KV;Ganesan LP;Crouser ED;Gunn JS;Turner J;Schlesinger LS;Mohler PJ;Rajaram MV
通讯作者：
Rajaram MV
DOI：
10.1186/cc5055
发表时间：
2006
期刊：
Critical care (London, England)
影响因子：
--
作者：
Cavaillon JM;Adib-Conquy M
通讯作者：
Adib-Conquy M
影响因子：
8.8
作者：
BarrientosVega, R;SanchezSoria, MM;AyensaRincon, A
通讯作者：
AyensaRincon, A
影响因子：
38.9
作者：
Chishti, AD;Shenton, BK;Baudouin, SV
通讯作者：
Baudouin, SV
影响因子：
--
作者：
Kobayashi E;Suzuki T;Yamamoto M
通讯作者：
Yamamoto M