BACKGROUND As subarachnoid hemorrhage due to rupture of an intracranial aneurysm (IA) has quite a poor outcome despite of an intensive medical care, development of a novel treatment targeting unruptured IAs based on the correct understanding of pathogenesis is mandatory for social health. METHODS Using previously obtained gene expression profile data from surgically resected unruptured human IA lesions, we selected G-protein coupled receptor 120 (GPR120) as a gene whose expression is significantly higher in lesions than that in control arterial walls. To corroborate a contribution of GPR120 signaling to the pathophysiology, we used an animal model of IAs and examine the effect of a GPR120 agonist on the progression of the disease. IA lesion was induced in rats through an increase of hemodynamic stress achieved by a one-sided carotid ligation and induced hypervolemia. Eicosapentaenoic acid (EPA) was used as an agonist for GPR120 in this study and its effect on the size of IAs, the thinning of media, and infiltration of macrophages in lesions were examined. RESULT EPA administered significantly suppressed the size of IAs and the degenerative changes in the media in rats. EPA treatment also inhibited infiltration of macrophages, a hallmark of inflammatory responses in lesions. In in vitro experiments using RAW264.7 cells, pre-treatment of EPA partially suppressed lipopolysaccharide-induced activation of nuclear factor-kappa B and also the transcriptional induction of monocyte chemoattractant protein 1 (MCP-1), a major chemoattractant for macrophages to accumulate in lesions. As a selective agonist of GPR120, TUG-891, could reproduce the effect of EPA in RAW264.7 cells, EPA presumably acted on this receptor to suppress inflammatory responses. Consistently, EPA remarkably suppressed MCP-1 expression in lesions, suggesting the in vivo relevance of in vitro studies. CONCLUSIONS These results combined together suggest the potential of the medical therapy targeting GPR120 or using EPA to prevent the progression of IAs.

中文翻译：

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二十碳五烯酸可防止大鼠颅内动脉瘤的发展。

背景技术由于尽管进行了深入的医疗护理，但由于颅内动脉瘤（IA）破裂导致的蛛网膜下腔出血的效果相当差，因此，基于对发病机理的正确理解，开发针对未破裂IA的新型治疗方法对于社会健康是必不可少的。方法使用先前从手术切除的未破裂人IA病变中获得的基因表达谱数据，我们选择G蛋白偶联受体120（GPR120）作为其病变中的表达明显高于对照动脉壁的基因。为了证实GPR120信号传导对病理生理的贡献，我们使用了IAs的动物模型并研究了GPR120激动剂对疾病进展的影响。通过单侧颈动脉结扎和高血容量导致的血流动力学压力增加，可在大鼠中诱发IA病变。二十碳五烯酸（EPA）在本研究中用作GPR120的激动剂，并检查了其对IAs大小，介质变薄和巨噬细胞浸润的影响。结果EPA给药显着抑制了IAs的大小和大鼠培养基的变性变化。EPA处理还抑制了巨噬细胞的浸润，巨噬细胞是病变中炎症反应的标志。在使用RAW264.7细胞的体外实验中，EPA的预处理部分抑制了脂多糖诱导的核因子-κB的活化以及单核细胞趋化蛋白1（MCP-1）的转录诱导，单核细胞趋化蛋白1是巨噬细胞积累的主要趋化因子。在病变中。作为GPR120的选择性激动剂TUG-891，可以在RAW264.7细胞中重现EPA的作用，因此EPA可能作用于该受体以抑制炎症反应。一致地，EPA显着抑制了病变中MCP-1的表达，提示了体外研究的体内相关性。结论这些结果加在一起表明，针对GPR120或使用EPA的药物治疗有可能预防IAs的发展。