老年急性脑梗死患者血清circTTC3和miR-138-5p水平变化及意义 (1).pdf

疑难病杂志2 0 2 4年5月第2 3卷第5期Chin J Diffic and Compl Cas,May 2024,Vol.23,No.5 537D01】10.396 9/j.i s s n.16 7 1-6 450.2 0 2 4.0 5.0 0 6老年急性脑梗死患者血清 circTTC3 和miR-138-5p水平变化及意义论著临床古红，张奕玲，赵宇，张婷，沈恺基金项目：四川省自然科学基金资助项目（2 0 2 2 NSFSC1463）作者单位：6 10 0 0 0 成都，四川大学华西医院老年医学中心/干部医疗科（古红），神经内科（张奕玲、赵宇），老年内科（张婷），血液科(沈恺)通信作者：沈恺，E-mail:【摘要】目的探究老年急性脑梗死（ACI）患者血清环状RNA TTC3（c i r c T T C3）和微小RNA-138-5p（mi R-138-5p）水平变化及意义。方法选取2 0 2 1年9月一2 0 2 3年9月四川大学华西医院老年医学中心/干部医疗科诊治老年ACI患者12 8 例（ACI组），根据美国国立卫生研究院卒中量表（NIHSS)分为轻度亚组42 例、中度亚组49例和重度亚组37 例,同期医院门诊体检的健康人员12 0 例作为健康对照组；采用实时荧光定量PCR法测定血清circTTC3和miR-138-5p表达水平,Pearson 法分析老年ACI患者血清 circTTC3和miR-138-5p的相关性,Spearman法分析老年 ACI患者血清 circTTC3和 miR-138-5p表达水平与 NIHSS评分相关性,受试者工作特征(ROC)曲线分析血清 circTTC3和miR-138-5p表达水平对老年ACI患者神经缺损程度的诊断价值。结果与健康对照组比较,ACI 组血清 circTTC3表达水平升高，miR-138-5p降低（t/P=17.207/0.001、16.2 39/0.0 0 1）。血清circTTC3水平比较，轻度亚组 中度亚组 中度亚组 重度亚组（F/P=26.579/0.001、10 5.935/0.001）。老年ACI患者血清circTTC3表达水平与NIHSS评分呈正相关（r=0.521,P0.001），与大脑中动脉（MCA）、大脑前动脉（ACA）血流速度呈负相关（r=-0.425、-0.392,P均 0.0 0 1）;miR-138-5p表达水平与NIHSS评分呈负相关(r=-0.785,P0.001),与MCA、A C A 血流速度呈正相关(r=0.571、0.6 35,P均 0.0 0 1）。circTTC3、m iR-138-5p及二者联合诊断ACI神经缺损程度的AUC分别为0.8 17、0.8 10 0.8 7 8，二者联合诊断价值优于单独诊断（Z/P=2.106/0.035、2.40 6/0.0 16）。结论老年ACI患者血清circTTC3表达水平升高，miR-138-5p表达水平降低，二者与患者病情的严重程度密切相关,可能作为 ACI病情诊断、治疗相关的作用靶点。【关键词】急性脑梗死；环状RNATTC3;微小RNA-138-5p;神经功能；老年人【中图分类号】R743.3;R446.11*2Changes and significance of serum circTTC3 and miR-138-5p levels in elderly patients with acute cerebral infarctionGu Hong,Zhang Yiling,Zhao Yu,Zhang Ting,Shen Kai.*Geriatrics Center,West China Hospital of Sichuan University,Sichuan Province,Chengdu 610000,ChinaFunding program:Sichuan Natural Science Foundation(2022NSFSC1463)Corresponding author:Shen Kai,E-mail:545235787 Abstract)Objective To investigate the changes and significance of serum cyclic RNA TTC3(circTTC3)andmicroRNA-138-5p(miR-138-5p)levels in elderly patients with acute cerebral infarction(ACI).Methods From September2021 to September 2023,the Geriatric Medicine Center/Cadre Medical Department of West China Hospital of Sichuan Univer-sity treated 128 elderly patients with ACI(ACI group),according to the National Institute of Health Stroke Scale(NIHSS),elderly ACI patients were separated into a mild group of 42 cases,a moderate group of 49 cases,and a severe group of 37cases,meantime,120 healthy individuals who came to the outpatient clinic for physical examination were regarded as acontrol group,real-time fluorescence quantitative PCR method was applied to determine the expression levels of circTTC3and miR-138-5p in serum,Pearson method was applied to analyze the correlation between serum circTTC3 and miR-138-5p inelderly ACI patients,Spearman method was applied to analyze the correlation between serum circTTC3 and miR-138-5plevels and NIHSS scores in elderly ACI patients,ROC curve was applied to analyze the diagnostic value of serum circTTC3【文献标识码 A538and miR-138-5p expression levels in elderly ACI patients,Results Compared with the control group,the expression level ofcircTTC3 in serum of ACI group was increased,and miR-138-5p was decreased(t/P=17.207/0.001,16.239/0.001).Theserum circTTC3 level in mild subgroup was lower than that in moderate subgroup than that in severe subgroup,and the ex-pression level of miR-138-5p in mild subgroup was higher than that in moderate subgroup than that in severe subgroup(F/P=26.579/0.001,105.935/0.001).Serum circTTC3 expression level in elderly ACI patients was positively correlatedwith NIHSS score(r=0.521,P0.001),and negatively correlated with MCA and ACA(r=-0.425,-0.392,all P0.001).Theexpression level of miR-138-5p was negatively correlated with NIHSS score(r=-0.785,P0.001),and positively correlatedwith MCA and ACA(r=0.571,0.635,all P0.05）,具有可比性。本研究经医院伦理委员会审批通过（2 0 2 1-0 8 18），受试者及家属均知情同意并签署同意书。1.2病例选择标准（1)纳人标准:ACI诊断符合中国急性缺血性脑卒中诊治指南2 0 18 中诊断标准 8 ;年龄6 0 岁;所有 ACI患者均为首次发病。(2)排除标准：合并有严重颅脑损伤患者;合并有严重血液系统疾病患者;合并有恶性肿瘤患者;合并有严重心功能、肝肾功能障碍患者。1.3观测指标与方法1.3.1血清circTTC3和miR-138-5p表达水平测定：于ACI患者人院和健康人员体检当日清晨抽取空腹静脉血3ml,静置（室温）15min后,离心收集上层血清，于8 0 条件下冻存备检。采用实时荧光定量PCR法测定血清circTTC3和miR-138-5p表达水平。采用 TRIzol 试剂（北京普利莱基因技术有限公司,货号R1030）进行总RNA提取，按照逆转录试剂盒Pri-meScriptTMRT（日本Takara公司，货号RR037A）说明书进行反转录合成cDNA。引物序列见表1。分别以GAPDH 和 U6 为内参进行 PCR 扩增,2-ACT法进行计算circTTC3和miR-138-5p相对表达水平。所有实验至少重复3次。1.3.2NIHSS评分：按照美国国立卫生研究院卒中量表(National Institute of Health stroke scale,NIHSS)对老年ACI患者入组时神经系统缺损进行评分，分为轻度神经功能障碍（15分）9,并将老年ACI患者分为轻度亚组42 例、中度亚组49例和重度亚组37 例。表1circTTC3和miR-138-5p 引物序列Tab.1CircTTC3 and miR-138-5p primer sequences基因上游引物circTTC35-CACGATTGCATCCCTG-5TCTG-3miR-138-5p 5-AGTCTGGTGTTGTGAA-TCAGGC-3GAPDH5-AAGCCACCCCACTTCT-CTCTAA-3U65-CTCGCTTCGGCAGCAC-5-AACGCTTCACGAATTTG-A-31.3.3血流检测：老年ACI 患者入组时,采用经颅多普勒超声检测大脑中动脉（MCA）、大脑前动脉（ACA）血流速度。1.4统计学方法采用SPSS25.0软件进行数据处理和分析。符合正态分布的计量资料以xs表示，2组间比较采用独立样本t检验，3组比较采用单因素方差分析,进一步两两比较采用SNK-q检验；Pearson法分析老年ACI患者血清circTTC3 和miR-138-5p的相关性;Spearman 法分析老年 ACI 患者血清 circTTC3和miR-138-5p表达水平与NIHSS评分相关性;受试者工作特征（ROC）曲线分析血清circTTC3和miR-138-5p表达水平对老年ACI患者神经缺损程度的诊断价值。P0.05为差异有统计学意义。2结果2.12组血清circTTC3和miR-138-5p表达水平比较与健康对照组比较,ACI 组血清circTTC3表达水平升高,miR-138-5p降低(P0.01),见表2。表 2 健康对照组与 ACI 组血清 circTTC3和miR-138-5p 表达水平比较(xs)Tab.2Comparison of serum circTTC3 and miR-138-5p expres-sion levels between healthy control group and ACI group组别例数健康对照组120ACI组128值P值2.2ccircTTC3和miR-138-5p靶向关系预测CORI 数据库（https:/ of target binding sites for circTTC3 and miR-138-5p下游引物5-ACTGTCACGTTTCAAGAT-CACT-35-AACATGTACAGTCCATG-GATG-3*5-AATGCTATCACCTCCCC-TGTGT-3CGT-3circTTC31.02 0.201.69 0.3817.2070.0012.3老年ACI患者不同亚组血清circTTC3和miR-138-5p表达水平比较血清circTTC3水平比较,轻度亚组 中度亚组 中度亚组 重度亚组（P均 中度亚组 重度亚组(P均 0.0 1),见表4。表4老年ACI患者不同亚组血流速度比较（s,cm/s）Tab.4Comparison of blood flow velocity in elderly ACI patientsin 3 subgroups组别例数轻度亚组42中度亚组49重度亚组37F值P值2.5血清circTTC3和miR-138-5p表达水平与NIHSSmiR-138-5p1.05 0.240.64 0.1516.2390.001J经EN-circTTC31.55 0.161.70 0.181.84 0.1926.5790.001MCA53.17 6.1942.19 5.4733.53 4.21131.7410.001评分、血流速度的相关性老年 ACI 患者血清中circTTC3表达水平与 NIHSS 评分呈正相关，与MCA、ACA血流速度呈负相关；miR-138-5p表达水平与NIHSS评分呈负相关，与MCA、A CA 血流速度呈正相关(P0.01),见表5。2.6血清circTTC3和miR-138-5p表达水平诊断老年ACI神经缺损程度的价值绘制血清circTTC3和miR-138-5p表达水平诊断老年ACI神经缺损程度的miR-138-5p0.76 0.080.63 0.070.52 0.07105.9350.001MCA、ACA43.17 5.9135.18 4.8629.54 3.1579.8070.001540表5血清circTTC3和miR-138-5p表达水平与 NIHSS 评分及血流速度的相关性Tab.5 Correlation between serum circTTC3 and miR-138-5p ex-pression levels and NIHSS score and blood flow velocity项目P值NIHSS评分0.521MCA血流速度-0.425ACA血流速度0.392价值ROC曲线，并计算曲线下面积（AUC），结果显示：circTTC3、m iR-138-5p 及二者联合诊断ACI患者神经缺损程度的AUC分别为0.8 17、0.8 10、0.8 7 8，二者联合诊断价值优于单独诊断（Z=2.106、2.40 6,P=0.035,0.016），见图2、表6。1.0F0.8F0.6F0.4H0.20图2 血清circTTC3和miR-138-5p表达水平诊断老年ACI神经缺损程度的ROC曲线Fig.2ROC curve of serum circTTC3 and miR-138-5p expressionlevels for diagnosing the degree of ACI nerve defect in eld-erly patients表6 血清 circTTC3和miR-138-5p表达水平诊断老年 ACI 神经缺损程度的价值分析Tab.6 Value analysis of serum circTTC3 and miR-138-5p expres-sion levels in diagnosing the degree of ACI nerve defect inelderly patients指标截断值AUCcircTTC31.68miR-138-5p0.66二者联合3 讨 论ACI是一种临床上较为常见的脑部血管疾病,其疑难病杂志 2 0 2 4 年5 月第2 3卷第5期Chin J Diffic and Compl Cas,May2024,Vol.23,No.5发生主要是由于高血压、糖尿病等多种病因引起的脑部血循环障碍,脑组织缺氧、缺血导致脑组织出现局部坏死及神经功能缺损，老年人是主要的发病群体 10-。随着基因诊断技术的不断进步,血清基因诊circTTC3miR-138-5p值P值0.0010.0010.001-circTTC3-miR-138-5p一二者联合一参考线10.20.40.61-特异度95%CI敏感度特异度约登指数0.8170.739 0.8800.8100.731 0.8740.8780.8080.929断是早期发现ACI较为灵敏的诊断手段，对其早干值0.7850.0010.5710.0010.6350.0010.81.00.6510.8570.5080.7330.738 0.4710.7210.9520.673预、早治疗具有重要意义。环状RNA（c i r c R NA s）已经被确定为一种没有5-3聚腺苷化或极性尾部的环状结构的关键调控RNA，其中一个重要生物学功能是充当分子海绵，在短时间内显著改变miRNA水平,与缺血性脑卒中或急性脑梗死密切相关 12 。据报道,circRNAs 能够调节缺血性脑卒中后神经干细胞（neural stem cells,NSCs）的功能恢复 13。Yu等 14 研究显示,circTTC3 能够通过下调miR-449a保护细胞免受缺氧损伤。Yang等 15 通过建立大脑中动脉闭塞/抑制和缺氧缺糖再灌注小鼠模型，发现这2 种类型小鼠的星形胶质细胞中 circTTC3的表达上调,这导致NSCs功能障碍，促使星形胶质细胞损伤。提示circTTC3在多种疾病中均可发挥重要作用。本研究显示,ACI 组血清 circTTC3 高表达,且神经缺损程度越严重其水平越高，与NIHSS评分、MCA、ACA 血流速度均显著相关,提示 circTTC3可能与 ACI的发生及病情进展有关,且与患者的神经缺损及脑血流水平均在一定程度上具有相关性,推测circTTC3表达上调能够抑制NSCS 的增殖和分化,促使ACI患者脑缺血再灌注损伤,加重ACI病情。miRNAs 作为一种单链的非编码RNA,能够通过与靶基因(mRNA)结合参与到调控相关基因的转录后表达水平 16 。既往研究发现,miRNAs 在 ACI 患者血清中异常表达,能够作为疾病诊断以及预后评估的标志物 17-19。Tang等 2 0 研究显示miR-138 对脑缺血再灌注损伤大鼠模型具有保护作用。Li 等 2 1 通过大脑动脉闭塞和和缺氧缺糖再灌注小鼠模型进行体外实验，发现miR-138-5p能够被lncRNAH19负调控，下调miR-138-5p表达并作用于其靶标p65（核因子NF-kBp65亚基），从而促进缺血再灌注损伤诱导的炎性反应,加重缺血性卒中的神经损伤。然而关于miR-138-5p在ACI患者血清中的表达变化的研究较少。本研究结果显示,ACI组血清miR-138-5p低表达,且随神经缺损程度的增加而降低，与NIHSS 评分及 MCA、ACA血流速度均具有相关性,提示miR-138-5p可能参与老年 ACI的发生发展,且其与 ACI 患者的神经缺损严重程度及脑血流速度均有关,推测可能是miR-138-5p表达下调,其对脑缺血再灌注损伤的保护作用被抑制,从而增强了炎性因子的分泌及释放,促进ACI病疑难病杂志2 0 2 4 年5月第2 3卷第5期Chin J Diffic and Compl Cas,May2024,Vol.23,No.5情发展。环状RNA可以与特定的miRNA相互作用,阻止miRNA的翻译,这一过程涉及细胞增殖、凋亡、自噬等生物学过程和心血管疾病、神经系统疾病、癌症等疾病的病理过程 2-2 4 。Hu 等 2 5 的研究发现环状 RNACdrlas通过PARP和 SP1 抑制miR-7a表达,在心肌梗死损伤加重时诱导心肌细胞调亡。本研究首先通过网站预测发现 circTTC3和miR-138-5p之间存在靶向关系,又进行了相关性分析,结果表明血清 circTTC3 和miR-138-5p表达水平呈负相关，提示miR-138-5p可能是circTTC3 的负调控因子。因此,本研究推测 circT-TC3通过靶向负调控miR-138-5p表达以参与ACI病情进展，circTTC3表达水平升高，与miR-138-5p特定位点相结合,抑制其翻译过程,从而抑制了对脑缺血再灌注损伤的保护作用,增强 NSCs功能障碍,导致神经缺损程度增加。同时,本研究构建ROC曲线探究血清circTTC3和miR-138-5p在ACI患者中的临床应用价值,结果显示,circTTC3 和miR-138-5p对 ACI 患者的神经缺损程度具有一定的诊断价值，提示二者可能作为 ACI患者病情发展进程评估的标志物。综上，老年ACI患者血清circTTC3表达水平升高,miR-138-5p表达水平降低,二者与患者病情的严重程度密切相关,可能作为 ACI神经缺损程度诊断、治疗相关的作用靶点。本研究中样本量较少,研究结果可能存在一定的偏差，有待增加样本量作更深人研究。利益冲突：所有作者声明无利益冲突作者贡献声明古红：设计研究方案，实施研究过程，论文撰写；张奕玲、赵宇：提出研究思路，分析试验数据，论文审核；张婷：进行统计学分析；沈恺：实施研究过程，资料搜集整理，论文修改参考文献1聂晓慧，薛茜,寇文辉,等.急性脑梗死患者外周血LncRNA-NEAT1,miR-93-5p表达水平及临床意义 J.现代检验医学杂志，2022,37(6):94-98.D0I:10.3969/j.issn.1671-7414.2022.06.017.2张燕，谢曙文，韩能.急性脑梗死患者血清神经元特异性烯醇化酶和同型半胱氨酸水平变化及其临床意义 J.临床与病理杂志,2 0 2 1,41(2):30 4-30 9.D01;10.3978/j.issn.2095-6959.2021.02.010.3Huang Z,Ma W,Xiao J,et al.CircRNA_0092516 regulates chondro-cyte proliferation and apoptosis in osteoarthritis through the miR-337-3p/PTEN axis J.Biochem,2021,169(4):467-475.D0I:10.1093/jb/mvaal19.4Cai L,Qi B,Wu X,et al.Circular RNA Ttc3 regulates cardiac func-tion 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