A Pentapeptide Monocyte Locomotion Inhibitory Factor Protects Brain Ischemia Injury by Targeting the eEF1A1/Endothelial Nitric Oxide Synthase Pathway
A Pentapeptide Monocyte Locomotion Inhibitory Factor Protects Brain Ischemia Injury by Targeting the eEF1A1/Endothelial Nitric Oxide Synthase Pathway
复制标题
DOI：
10.1161/strokeaha.112.657908
复制
发表时间：
2012-10
期刊：
影响因子：
8.3
通讯作者：
Yuefan Zhang;Jun Chen;Fan Li;Dong Li;Qi-Xing Xiong;Yang Lin;Dazhi Zhang;Xiao-Fan Wang;Pengyuan Yang;Y. Rui
中科院分区：
文献类型：
--
作者：
Yuefan Zhang;Jun Chen;Fan Li;Dong Li;Qi-Xing Xiong;Yang Lin;Dazhi Zhang;Xiao-Fan Wang;Pengyuan Yang;Y. Rui
背景和目的-缺血性卒中是世界范围内死亡的主要原因，但缺乏可行的治疗或治疗靶点。单核细胞运动抑制因子（MLIF）是溶组织内阿米巴（Entamoeba histolytica）在无菌培养条件下产生的一种热稳定的小分子五肽，被认为具有保护脑缺血损伤的作用，但其作用机制尚不清楚。在这项研究中，我们进一步研究了MLIF在脑缺血中保护作用的机制。方法采用大鼠大脑中动脉闭塞模型，观察MLIF对在体脑缺血的影响。为了确定MLIF在脑内皮细胞中的靶点，我们对生物素标记的MLIF进行了免疫沉淀和质谱分析。结果- MLIF可以在体内保护脑免受缺血性损伤，减少缺血体积，延长生存期，改善神经功能结局。体外研究表明，MLIF通过抑制病理性炎症粘附分子的表达和增强血管内皮细胞一氧化氮合酶的表达和一氧化氮的释放而显示出保护作用。靶点筛选实验证明了MLIF与核糖体蛋白翻译延伸因子eEF 1A 1的结合。MLIF通过稳定内皮型一氧化氮合酶mRNA而增强内皮型一氧化氮合酶的表达，而eEF 1A 1被证明是这种增强表达所必需的。敲低eEF 1A 1或抑制内皮型一氧化氮合酶可减弱MLIF介导的粘附分子表达抑制。结论：在这项研究中，我们确定了一种新的潜在的可靶向机制，该机制是MLIF通过eEF 1A 1/内皮型一氧化氮合酶途径对脑缺血的保护作用。
Background and Purpose— Ischemic stroke is a major cause of death worldwide but lacks viable treatment or treatment targets. Monocyte locomotion inhibitory factor (MLIF) is a small heat-stable pentapeptide produced by Entamoeba histolytica in axenic culture, which is supposed to protect the brain from ischemic injury; the mechanism, however, remains unknown. In this study, we further investigated the mechanism underlying the protective role of MLIF in brain ischemia. Methods— A middle cerebral artery occlusion model in rats was used for detecting the effect of MLIF in the brain ischemia in vivo. To identify targets of MLIF in brain endothelial cells, we performed immunoprecipitation of biotin-conjugated MLIF and mass spectrometry. Results— MLIF can protect the brain from ischemic injury in vivo, yielding decreased ischemic volume, prolonged survival, and improved neurological outcome. In vitro studies showed that MLIF displayed protective effects through inhibition of expression of pathological inflammatory adhesion molecules and enhancing endothelial nitric oxide synthase expression and nitric oxide release in the cerebrovascular endothelium. The target screening experiments demonstrated binding of MLIF to the ribosomal protein translation elongation factor eEF1A1. MLIF enhanced endothelial nitric oxide synthase expression through stabilization of endothelial nitric oxide synthase mRNA, and eEF1A1 was shown to be necessary for this enhanced expression. Knockdown of eEF1A1 or inhibition of endothelial nitric oxide synthase attenuated MLIF-mediated inhibition of adhesion molecule expression. Conclusions— In this study, we identified a new potential pharmacologically targetable mechanism underlying MLIF's protective effects in brain ischemia through the eEF1A1/endothelial nitric oxide synthase pathway.