醋酸脱氧皮质酮(DOCA)加高盐诱导动脉瘤发生发展的作用及潜在机制  

The role and potential mechanism of deoxycorticosterone acetate plus salt-induced aneurysm development

作　　者：吴献贤 刘星 张娜[3] 李雨涵 杜星辰 杨志伟 WU Xianxian;LIU Xing;ZHANG Na;LI Yuhan;DU Xingchen;YANG Zhiwei(Institute of Laboratory Animal Sciences,Chinese Academy of Medical Sciences(CAMS)Comparative Medicine Center,Peking Union Medical College(PUMC),Key Laboratory of Human Disease Comparative Medicine,National Health Commission,Bejing 100021,China;Beijing Engineering Research Center for Laboratory Animal Models of Human Critical Diseases,Bejjing 100021;Ningxia Medical University,Yinchuan 750004)

机构地区：[1]中国医学科学院医学实验动物研究所,北京协和医学院比较医学中心,国家卫生健康委员会人类疾病比较医学重点实验室,北京100021 [2]北京市人类重大疾病实验动物模型工程技术研究中心,北京100021 [3]宁夏医科大学,银川750004

出　　处：《中国比较医学杂志》2021年第1期27-34,共8页Chinese Journal of Comparative Medicine

基　　金：中国医学科学院医学与健康科技创新工程重大协同创新项目(CIFMS,2016-I2M-1-016);国家自然科学基金青年项目(81800402)。

摘　　要：目的探讨醋酸脱氧皮质酮(DOCA)加高盐在不同时间点对腹主动脉瘤的诱导作用,及潜在分子机制。方法将10月龄C57BL/6J小鼠分为两组:高盐组(HS),DOCA加高盐组(DOCA+HS)。两组小鼠在接受不同的处理一周,两周,三周时分别超声并取材,观察腹主动脉的扩张情况和动脉瘤的形成情况;HE染色,Masson染色和弹力纤维染色检测腹主动脉病理状态、胶原沉积和弹力纤维断裂情况;免疫组织化学法检测平滑肌细胞降解,腹主动脉炎症细胞浸润;RT-PCR检测炎症因子、抗炎因子的表达;转录组测序(RNA-Sequence)分析比较两组小鼠处理三周时动脉组织差异性表达基因及差异表达基因富集的信号通路。结果与单纯高盐饮水组相比,DOCA加高盐处理一周无法诱导小鼠腹主动脉瘤的形成,处理两周能显著诱导动脉瘤的发生,动脉瘤发生率为44%,处理三周时动脉瘤发生率为65%;DOCA加高盐处理两周和三周后,腹主动脉处胶原沉积增多,出现弹力纤维断裂,平滑肌细胞降解;炎症细胞浸润明显增多,浸润的炎症细胞以巨噬细胞和T细胞为主;炎症因子表达明显增加,抗炎因子表达下降;进一步的转录组测序结果表明两组小鼠在处理三周后差异表达的基因主要富集在免疫系统和代谢通路中,并且发现介导白细胞粘附的关键分子PSGL-1在DOCA加高盐处理三周后表达明显升高。结论 DOCA加高盐处理两周即可诱导小鼠腹主动脉瘤的发生,PSGL-1及其介导的炎症反应可能在其中发挥着重要作用。Objective To investigate the induction of abdominal aortic aneurysm by DOCA plus high salt at different time points and the underlying molecular mechanism.Methods Ten-month-old C57 BL/6 J mice were divided into two groups:a high-salt group(HS)and a DOCA plus high-salt group(DOCA+HS).Each group received the designated treatments for 1 week,2 weeks,and 3 weeks.At the end of treatment,the mice were anesthetized with isoflurane followed by ultrasonography and aorta collection to observe abdominal aorta expansion and aneurysm formation.H&E staining,Masson’s staining,and elastic fiber staining were performed to detect pathological changes,collagen deposition,and elastic fiber fragmentation,respectively.Immunohistochemistry was used to detect abdominal aortic inflammatory cell infiltration,and RT-PCR was used to detect the m RNA expression of inflammatory and anti-inflammatory factors.RNA sequencing was conducted to analyze the differentially-expressed genes and the enrichment signaling pathways of these genes in the arterial tissues of the two groups of mice after 3 weeks of treatment.Results Compared with the HS group,DOCA+HS treatment for 1 week did not induce the formation of abdominal aortic aneurysms in mice,but after 2 weeks of treatment,the mice began to form aortic aneurysms.The incidence of aortic aneurysm was 44%at week 2 and 65%at week3.With increased duration of DOCA+HS treatment,collagen deposition in the abdominal aorta increased,and elastic fiber fragmentation was observed.Meanwhile,high inflammatory cell infiltration(mainly macrophages and T cells)was observed in the abdominal aorta of mice after treatment with DOCA+HS for 2 weeks and 3 weeks.The m RNA levels of inflammatory factors increased significantly,while the m RNA levels of anti-inflammatory factors decreased.Additional transcriptome sequencing result showed that the differentially-expressed genes in the two groups of mice after 3 weeks of treatment were enriched mainly in the immune system and metabolic pathways,and that levels of the key mol

关 键 词：动脉瘤 醋酸脱氧皮质酮 高盐 炎症反应 

分 类 号：R-33[医药卫生]