Eicosapentaenoic acid prevents the progression of intracranial aneurysms in rats
Eicosapentaenoic acid prevents the progression of intracranial aneurysms in rats
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DOI：
10.1186/s12974-020-01802-8
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发表时间：
2020-04-24
影响因子：
9.3
通讯作者：
Aoki, Tomohiro
中科院分区：
文献类型：
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作者：
Abekura, Yu;Ono, Isao;Aoki, Tomohiro
背景颅内动脉瘤破裂所致的蛛网膜下腔出血虽经严密治疗，但预后较差，因此在正确认识其发病机制的基础上，开发针对未破裂性颅内动脉瘤的新型治疗方法对社会健康具有重要意义。方法利用先前从手术切除的未破裂的人IA病变中获得的基因表达谱数据，我们选择了g蛋白偶联受体120 （GPR120）作为基因，该基因在病变中的表达明显高于对照动脉壁。为了证实GPR120信号对病理生理的贡献，我们使用了IAs的动物模型，并检查了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引起的血流动力学应激增加，在大鼠中诱导IA病变。本研究采用二十碳五烯酸（Eicosapentaenoic acid， EPA）作为GPR120的激动剂，观察其对IAs大小、介质变薄和病变中巨噬细胞浸润的影响。结果EPA能明显抑制大鼠IAs的大小和介质的退行性改变。EPA治疗还抑制巨噬细胞的浸润，巨噬细胞是病变中炎症反应的标志。在RAW264.7细胞的体外实验中，EPA预处理部分抑制了脂多糖诱导的核因子κ B的激活以及单核细胞趋化蛋白1 （MCP-1）的转录诱导，MCP-1是巨噬细胞在病变中积聚的主要趋化剂。作为GPR120的选择性激动剂，TUG-891可以在RAW264.7细胞中复制EPA的作用，EPA可能通过作用于该受体抑制炎症反应。一致地，EPA显著抑制病变中MCP-1的表达，提示体外研究的体内相关性。结论以GPR120或EPA为靶点的药物治疗可预防IAs的进展。
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.