CN117305431A - lncRNA NONMMUT067673.2作为生物标志物在用于制备慢性心力衰竭和心肌纤维化检测试剂或抑制剂中的应用 - Google Patents
lncRNA NONMMUT067673.2作为生物标志物在用于制备慢性心力衰竭和心肌纤维化检测试剂或抑制剂中的应用 Download PDFInfo
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Abstract
本发明涉及生物技术领域的lncRNANONMMUT067673.2作为生物标志物在用于制备慢性心力衰竭和心肌纤维化检测试剂或抑制剂中的应用。本发明发现了一种新的可以用于诊断及治疗的非编码RNA，即lncRNA NONMMUT 067673.2。所述lncRNA在慢性心衰小鼠左室组织和细胞纤维化模型中表达上调，有望运用于临床诊断。本发明还证明了所述lncRNA可同时上调CTGF和FN1，促进心脏成纤维细胞增殖与迁移，促进心肌纤维化，从而加重慢性心衰，破坏心室功能。本发明还提供了lncRNANONMMUT067673.2的抑制剂的应用，抑制剂可下调所述lncRNA水平，延缓心肌纤维化，心功能等临床指标也有所改善，可应用于临床治疗，具有临床转化价值。
Description
技术领域
本发明涉及生物技术领域，特别涉及lncRNA NONMMUT067673.2作为生物标志物在用于制备慢性心力衰竭和心肌纤维化检测试剂或抑制剂中的应用。
背景技术
心血管疾病是世界范围内死亡的首要原因，而心力衰竭是多种心血管疾病的临床表现及终末阶段，指各种原因导致的心脏结构和(或)功能的异常改变，使心室收缩和(或)舒张功能发生障碍，心输出量不能满足机体的需求，同时引起神经内分泌调节障碍，对心脏及全身各器官造成影响的一组复杂临床综合征。由于其高发病率和死亡率，心力衰竭是当今世界最严重的公共卫生问题之一。因此，对心力衰竭进行防治是改善心脏疾病患者预后的重要措施。根据其起病及病程发展速度，可将其分为急性和慢性心力衰竭。其中，慢性心衰发病缓慢，病程长，在临床十分常见。
慢性心力衰竭始于心肌损伤，从而出现心室扩大和(或)肥大，起初代偿机制尚能维持正常的心脏输出，但这些神经体液机制最终将导致细胞毒性，引起心肌纤维化，造成病理性心脏重塑。其中，心肌纤维化是一类主要变化，多项研究在慢性心衰晚期病人的心脏间质中观察到了心肌纤维化。其定义为细胞外基质蛋白的过度积聚，可导致收缩和舒张功能严重受损，与心功能不良直接相关，还可造成心律失常的风险增加。目前的一线药物可以减少心衰后的死亡，但难以治愈或逆转心衰。原因可能在于，这些治疗方案对于修复受损心肌、逆转心脏病理改变的作用仍是有限的。而逆转包括心肌纤维化在内的病理改变，则可能有望治愈心衰。
近年来，随着对心肌纤维化的机制研究日渐完善，已发现了RAAS、TGF-β、CTGF、表观遗传等纤维化治疗靶点，并开发了应用生物材料和心脏再生医学的新疗法。但上述疗法效果目前均相对有限，存在一定毒副作用，且大多仍处于临床前阶段。因此，目前依然缺乏有效的治疗方法来抑制或逆转心肌纤维化，而原因可能在于心肌纤维化所涉及的细胞类型和信号通路众多，单一手段难以取得良好的治疗效果。
目前，非编码RNA相关研究充满前景。近年来，越来越多研究表明，长非编码RNA(long noncoding RNA,lncRNA)，一种长度超过200个核苷酸的转录本，在多种生理和病理过程中可能起到关键作用。一系列研究已发现，lncRNA可促进心肌纤维化的发生发展，而在模型动物体内抑制促纤维化lncRNA可有效减轻心肌纤维化，改善心功能。此外，lncRNA的作用机制众多，可能同时参与多个基因的共同调控，开发基于lncRNA的疗法可能起到更好的疗效。然而，目前尚无相关治疗手段进入临床，且已有研究大多仅关注单一靶点，部分下游机制也尚不明确，因此，其疗效也无法确定，该治疗手段仍处在摸索阶段。
发明内容
本发明的目的是提供lncRNANONMMUT067673.2作为生物标志物在用于制备慢性心力衰竭和心肌纤维化检测试剂或抑制剂中的应用，以解决上述存在的技术问题，lncRNANONMMUT067673.2作为一种长非编码RNA，可作为诊断慢性心衰和心肌纤维化的标志物，与心室功能和心肌纤维化程度相关。同时，抑制lncRNANONMMUT067673.2的表达可抑制成纤维细胞的增殖与迁移，有效减轻心肌纤维化，改善心室功能，有望作为慢性心衰和心肌纤维化药物的新靶点，具有安全性和高度特异性等特点。
为了实现上述目的，本发明的技术方案是这样实施的：
lncRNANONMMUT067673.2作为生物标志物在用于制备慢性心力衰竭和心肌纤维化检测试剂或抑制试剂中的应用。
优选地，所述检测试剂包括检测lncRNANONMMUT067673.2的特异性引物对和GAPDH内参引物对；
所述特异性引物对的核苷酸序列包括如SEQ ID NO.3所示的上游引物和SEQ IDNO：4所示的下游引物；
所述GAPDH内参引物对的核苷酸序列包括如SEQ ID NO.1所示的上游引物和SEQID NO：2所示的下游引物。
优选地，所述检测试剂或抑制试剂选自包括RNA提取试剂、RNA反转录试剂、实时定量荧光PCR试剂中的一种。
优选地，所述检测试剂被用于制备检测慢性心力衰竭和心肌纤维化的试剂盒。
优选地，所述试剂盒为过PCR定量所述lncRNANONMMUT067673.2的检测试剂盒。
优选地，所述抑制剂用于抑制人体lncRNANONMMUT067673.2的表达水平；lncRNANONMMUT067673.2的核苷酸序列如SEQ ID NO.3和SEQ ID NO：4所示。
本发明发现了一种新的可以用于诊断及治疗的非编码RNA，即lncRNA NONMMUT067673.2。所述lncRNA在慢性心衰小鼠左室组织和细胞纤维化模型中表达上调，有望运用于临床诊断。本发明还证明了所述lncRNA可同时上调CTGF和FN1，促进心脏成纤维细胞增殖与迁移，促进心肌纤维化，从而加重慢性心衰，破坏心室功能。本发明还提供了lncRNANONMMUT067673.2的抑制剂的应用，抑制剂可下调所述lncRNA水平，延缓心肌纤维化，心功能等临床指标也有所改善，可应用于临床治疗，具有临床转化价值。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一种实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为慢性心衰小鼠和AngⅡ处理的成纤维细胞中lncRNA NONMMUT067673.2表达水平对比图；
其中，图1A中：qRT-PCR检测TAC组小鼠左室组织中的lncRNA表达水平，与Sham组比较，**p<0.01，n＝4；图1B中：检测AngⅡ组细胞中的lncRNA表达水平，与Control组比较，***p<0.001，n＝4。
图2为lncRNANONMMUT067673.2促进成纤维细胞增殖迁移从而促进纤维化的整体图表。
其中，图2A表示转染过表达质粒或siRNA后lncRNA的表达水平，与Control组比较，***p<0.001；与NC组比较，#p<0.05，###p<0.001，n＝3；图2B为CCK-8实验数据，与NC组比较，***p<0.001，n＝3；图2C和图2D为划痕实验数据，bar＝200μm；与oe-NC比较，***p<0.001；与si-NC比较，##p<0.01，n＝3；图2E和图2F表示转染过表达质粒或siRNA后通过qRT-PCR和WB检测CTGF和FN1的表达水平，与Control组比较，*p<0.05，***p<0.001；与NC组比较，#p<0.05，##p<0.01，###p<0.001，n＝3。
图3为干扰lncRNANONMMUT067673.2表达可减轻慢性心衰小鼠心肌纤维化并改善心功能的数据图表。
其中，图3A为心超测定小鼠左室EF和FS的结果，与Sham组比较，***p<0.001；与TAC组比较，###p<0.001，n＝4；图3B为qRT-PCR检测小鼠LV组织中ANP和BNP的表达水平，与Sham组比较，***p<0.001；与TAC组比较，#p<0.05，##p<0.01，###p<0.001，n＝4；图3C为COL1A1和α-SMA的表达水平，与Sham组比较，***p<0.001；与TAC组比较，##p<0.01，###p<0.001，n＝4；图3D为小鼠LV组织HE和Sirius Red染色照片，bar＝50μm；图3E-3F为qRT-PCR和WB检测CTGF和FN1的表达水平，与Sham组比较，***p<0.001；与TAC组比较，#p<0.05，##p<0.01，###p<0.001，n＝4。
具体实施方式
下面将结合本发明实施例及其附图，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
1，材料
雄性C57BL/6小鼠购自上海市吉辉实验动物饲养有限公司；AngⅡ购自美国Sigma公司；胎牛血清、DMEM/F12培养基、胰蛋白酶购自美国Gibco公司；双抗购自美国Hyclone公司；Neomyt Kit(细胞提取试剂盒)购自美国Cellutron公司；FastPure Cell/Tissue TotalRNA Isolation Kit(RNA提取试剂盒)、HiScript Ⅲ RT SuperMix for qPCR(RNA逆转录试剂盒)、ChamQ Universal SYBR qPCR Master Mix(qRT-PCR试剂盒)、CCK-8试剂盒购自南京诺唯赞生物科技股份有限公司；RIPA裂解液、PMSF、BCA蛋白浓度测定试剂盒、脱脂奶粉购自上海碧云天生物技术有限公司；CTGF和FN1兔抗体、HRP标记山羊抗兔二抗购自美国CellSignaling Technology公司；LipofectamineTM3000Reagent转染试剂盒购自美国Invitrogen公司；
riboFECTTM CP转染试剂盒、lncRNA NONMMUT067673.2引物、lncRNANONMMUT067673.2小干扰RNA(si-lnc067673.2)及阴性对照(si-NC)购自广州锐博生物科技有限公司；lncRNA NONMMUT067673.2的过表达质粒(oe-lnc067673.2)及阴性对照(oe-NC)购自上海市汉尹生物科技有限公司。生物安全柜购自博科生物产业有限公司；细胞培养箱购自益世科企业发展有限公司；低温离心机购自德国Eppendorf公司；实时荧光定量PCR仪购自美国Applied Biosystems公司；光学显微镜购自德国Leica公司。
2，方法
2.1动物模型的构建及分组
采用横向主动脉缩窄(transverse aortic constriction,TAC)小鼠模型模拟慢性心衰及心肌纤维化。阿佛丁(250mg/kg，腹腔注射)麻醉小鼠，胸骨左侧第二肋取小切口，打开胸腔，暴露主动脉弓。将6-0丝线穿过右无名动脉和左颈总动脉之间的主动脉弓，紧贴主动脉弓平行放置27G垫针，结扎主动脉弓后抽出垫针，形成主动脉弓缩窄，再次结扎后逐层关闭胸腔。假手术组(Sham)小鼠经历类似的程序，同期开胸并分离主动脉弓，但不结扎，未形成主动脉弓缩窄，余同手术组。术后维持小鼠体温直至其苏醒，放回笼中常规饲养。
2.2成纤维细胞纤维化模型的建立
用含10％胎牛血清、1％双抗的DMEM/F12培养基培养小鼠心脏成纤维细胞(mousecardiac fibroblasts,mCF)，置于37℃、5％CO2培养箱中培养，当细胞生长密度达80％时，即可进行细胞传代等操作。通过AngⅡ处理mCF刺激其增殖分化，提前接种mCF，在无血清培养基中饥饿24小时后，采用0.1mg/ml AngⅡ溶液诱导，构建细胞纤维化模型，继续培养24小时后可用于后续实验。
2.3成纤维细胞的转染
分别通过向mCF中转染lncRNA NONMMUT067673.2的小干扰RNA(si-lnc067673.2)和其过表达质粒(oe-lnc067673.2)实现lncRNA的抑制和过表达。选取生长状态良好的mCF进行培养，随机分为Control(空白对照)组、si-NC组、si-lnc067673.2组、oe-NC组、oe-lnc067673.2组，按说明书转染相应试剂，48小时后收集细胞进行后续实验。si-lnc067673.2和si-NC由广州锐博生物技术有限公司设计并合成，应用riboFECTTMCP转染试剂盒进行转染。oe-lnc067673.2及oe-NC由上海市汉尹生物科技有限公司设计并合成，应用LipofectamineTM3000Reagent转染试剂盒进行转染。
2.4CCK-8和划痕实验观察成纤维细胞增殖及迁移情况
选取生长状态良好的mCF进行培养，根据说明书应用CCK-8试剂盒检测各组mCF的细胞活力变化，以反映其增殖能力。此外，通过划痕实验检测细胞迁移能力，培养24小时后，用移液器吸头于孔中央轻划一条直线，并加入新鲜的培养基，分别在划痕操作后的0、6、12、24小时用显微镜拍摄照片，计算各组各个时间点的划痕面积，计算划痕愈合率，用以表示细胞迁移率。
2.5小鼠尾静脉注射
构建小鼠模型，随机分为Sham组、TAC组、TAC+si-lnc067673.2组、TAC+oe-lnc067673.2组。TAC术后4周起向小鼠尾静脉注射相应试剂调节lncRNA NONMMUT067673.2的表达水平，每周1次，共2周。其中，注射动物用siRNA以降低小鼠体内lncRNA的表达水平，siRNA由广州锐博生物技术有限公司设计并合成。此外，注射利用重组腺病毒构建的lncRNA过表达载体以升高小鼠体内lncRNA的表达水平，重组腺病毒由上海市汉尹生物科技有限公司设计并合成。TAC术后6周，对小鼠进行超声心动图检测，随后取小鼠心脏左心室(leftventricle,LV)组织，提取RNA和蛋白进行后续检测，并进行苏木素-伊红(HE)和天狼星红(Sirius Red)染色。
2.6qRT-PCR检测lncRNA NONMMUT067673.2mRNA表达水平
根据试剂盒说明书提取各组成纤维细胞和小鼠LV组织的总RNA，逆转录为cDNA后进行qRT-PCR检测。lncRNA NONMMUT067673.2引物由广州锐博生物技术有限公司合成，引物序列如下：
PCR反应体系如下：
PCR扩增程序如下：
反应后，确定循环阈值(Ct)，GAPDH作为内参，采用2-△△Ct法计算基因相对表达水平。
2.7Western Blotting(WB)检测CTGF、FN1蛋白表达水平
收集各组各组成纤维细胞和小鼠LV组织，利用RIPA裂解液提取蛋白，BCA法进行蛋白浓度测定，70℃金属浴10分钟变性，依次上样进行SDS-PAGE凝胶电泳，干转至NC膜，5％脱脂牛奶室温封闭2小时，TBST洗涤3次后分别加入1∶1000稀释的CTGF、FN1一抗4℃孵育过夜，TBST洗膜3次，使用1∶8000的辣根过氧化物酶标记二抗室温孵育2小时，TBST洗膜3次。最后在超灵敏多功能成像仪上显影，以β-actin为内参，进行灰度分析，计算蛋白相对表达水平。
2.8统计学分析
上述实验结果均为计数资料，结果均以平均值±标准差(x±SD)表示，由不少于三次重复的独立实验得出。统计学分析通过Graphpad Prism V9.0完成。首先通过Shapiro-Wilk检验评估数据是否符合正态分布，若符合正态分布，两组数据之间的统计学差异通过双尾Student’s t检验确定，三组及以上数据之间的差异通过单因素方差分析(one-wayANOVA)确定，然后进行Bonferroni事后检验。在非正态分布的数据中，两组间使用双尾Mann-Whitney U检验，三组及以上使用Kruskal-Wallis检验，然后进行Dunn事后检验。p<0.05，认为差异显著，具有统计学意义。
3结果
3.1慢性心衰小鼠和AngⅡ处理的成纤维细胞中lncRNANONMMUT067673.2表达升高
构建慢性心衰小鼠模型，6周后分离小鼠LV组织，提取总RNA，通过qRT-PCR检测lncRNA NONMMUT067673.2的表达水平，结果表明，相较Sham组，此lncRNA表达水平在TAC组小鼠中显著增加，见图1A。应用AngⅡ处理成纤维细胞，构建细胞纤维化模型，同样检测此lncRNA表达水平。结果发现，相较对照组，AngⅡ组的lncRNA表达水平显著升高，见图1B。上述结果表明，lncRNA NONMMUT067673.2可能与慢性心衰及心肌纤维化有关。
3.2lncRNA NONMMUT067673.2促进成纤维细胞增殖迁移从而促进纤维化
为了进一步明确lncRNA NONMMUT067673.2对于心肌纤维化的作用，在成纤维细胞中分别转染si-lnc067673.2、si-NC、oe-lnc067673.2、oe-NC并检测此lncRNA表达水平，结果表明，si-lnc067673.2和oe-lnc067673.2分别有效抑制和增加了lncRNA的表达，见图2A。分别通过CCK-8和划痕实验检测细胞的增殖与迁移能力，结果表明，过表达lncRNA可有效促进成纤维细胞的增殖与迁移，而抑制lncRNA起到相反作用，见图2B-D。通过qRT-PCR和WB检测CTGF和FN1的表达量，结果发现，lncRNA可升高CTGF和FN1的表达水平，见图2E-F。上述结果表明，lncRNA NONMMUT067673.2可促进CTGF和FN1的表达，促进成纤维细胞增殖和迁移，从而促进心肌纤维化。
3.3干扰lncRNA NONMMUT067673.2表达可减轻慢性心衰小鼠心肌纤维化并改善心功能
为进一步探究lncRNANONMMUT067673.2的体内作用，通过尾静脉注射调节小鼠体内lncRNA的表达水平，随后进行超声心动图检测，并取心脏提取RNA，进一步检测ANP和BNP表达水平，通过上述指标评价左室功能。结果表明，相较TAC组，进一步过表达lncRNA可破坏慢性心衰小鼠的左室功能，使得EF和FS升高，而ANP和BNP水平降低；而抑制lncRNA可有效恢复心功能，见图3A-B。此外，通过检测纤维化标志物(COL1A1和α-SMA)表达水平评价心肌纤维化程度，结果表明，过表达lncRNA可升高COL1A1和α-SMA的表达水平，而抑制lncRNA可有效降低其表达水平，见图3C。组织学染色也表明，过表达lncRNA后心肌纤维化程度加重，而抑制lncRNA减轻心肌纤维化，见图3D。随后，通过RT-qPCR和WB检测CTGF和FN1的表达水平，结果表明，过表达lncRNA可升高CTGF和FN1的表达，而抑制lncRNA可有效降低其表达水平，见图3E-F。综合上述结果，在体内，lnc067673.2可同样促进CTGF和FN1表达，加重心肌纤维化，在慢性心衰中进一步损伤左室功能；而抑制lnc067673.2表达可有效减轻心肌纤维化，缓解左室功能。
Claims (6)
1.lncRNA NONMMUT067673.2作为生物标志物在用于制备慢性心力衰竭和心肌纤维化检测试剂或抑制剂中的应用。
2.根据权利要求1所述的应用，其特征在于，所述检测试剂包括检测lncRNANONMMUT067673.2的特异性引物对和GAPDH内参引物对；
所述特异性引物对的核苷酸序列包括如SEQ ID NO.3所示的上游引物和SEQ ID NO：4所示的下游引物；
所述GAPDH内参引物对的核苷酸序列包括如SEQ ID NO.1所示的上游引物和SEQ IDNO：2所示的下游引物。
3.根据权利要求2所述的应用，其特征在于，所述检测试剂或抑制试剂选自包括RNA提取试剂、RNA反转录试剂、实时定量荧光PCR试剂中的一种。
4.根据权利要求3所述的应用，其特征在于，所述检测试剂被用于制备检测慢性心力衰竭和心肌纤维化的试剂盒。
5.根据权利要求4所述的应用，其特征在于，所述试剂盒为过PCR定量所述lncRNANONMMUT067673.2的检测试剂盒。
6.根据权利要求1所述的应用，其特征在于，所述抑制剂用于抑制人体lncRNANONMMUT067673.2的表达水平；lncRNA NONMMUT067673.2的核苷酸序列如SEQ ID NO.3和SEQ ID NO：4所示。
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