LncRNA在缺血性卒中中的作用机制研究
Study on the Mechanism of LncRNA in Ischemic Stroke
DOI: 10.12677/acm.2024.14113034, PDF, HTML, XML,   
作者: 黄文吉, 桑 爽:绍兴文理学院医学院,浙江 绍兴;姚超杰, 张小兵, 俞学斌*:绍兴市人民医院神经外科,浙江 绍兴
关键词: 长非编码RNA (LncRNA)缺血性脑卒中微肽作用机制综述Long Non-Coding RNAs (LncRNAs) Ischemic Stroke Micropeptide Mode of Action Overview
摘要: 缺血性脑卒中作为全球发病率、致残率最高的疾病之一。其会引起中枢神经系统功能障碍、神经炎症和神经元死亡等一系列病理生理改变,临床预后较差。长非编码RNA (LncRNA)作为非编码RNA家族中的一员,近些年在肿瘤、心血管疾病和神经退行性疾病等领域成为研究的热点。近期通过对缺血性卒中的细胞、动物模型以及临床患者的样本进行测序分析,均发现它们的LncRNA转录谱存在显著差异。进一步研究表明,表达异常的LncRNA参与了缺血性卒中引发的细胞凋亡、细胞自噬、免疫炎症、氧化应激以及血管生成等病理生理过程,并通过不同层面的调控机制对卒中的预后产生正面或负面的影响。本文将对LncRNA转录前后调控等机制进行探讨,以阐明LncRNA调控链与缺血性卒中转归之间的关系,为缺血性卒中患者治疗提供新的思路。
Abstract: Ischemic stroke, a global leader in both incidence and disability rates, triggers a cascade of pathological changes within the central nervous system: dysfunction, neuroinflammation, and neuronal loss, frequently accompanied by bleak prognoses. Among the non-coding RNA family, long non-coding RNAs (LncRNAs) have lately captivated scientific interest across disciplines like oncology, cardiovascular diseases, and neurodegeneration. Recent sequencing endeavors in cellular models, animal studies, and actual ischemic stroke patient samples have unveiled marked discrepancies in LncRNA expression patterns. Advancing these findings, it’s been elucidated that dysregulated LncRNAs are embroiled in the intricate mechanisms following stroke, such as cell death, autophagy, immune responses, and vascular formation, influencing recovery either detrimentally or beneficially through multifaceted regulatory pathways. This discourse delves into the intricacies of LncRNA modulation—genetic, transcriptional, and post-transcriptional—to illuminate how this regulatory network intersects with stroke outcomes, paving the way for innovative therapeutic strategies in ischemic stroke management.
文章引用:黄文吉, 姚超杰, 张小兵, 桑爽, 俞学斌. LncRNA在缺血性卒中中的作用机制研究[J]. 临床医学进展, 2024, 14(11): 1470-1477. https://doi.org/10.12677/acm.2024.14113034

1. 缺血性卒中与LncRNA概述

缺血性脑卒中具有高发病率、高致残率、高死亡率、高复发率、高经济负担五大特点,在全球范围内造成了沉重的疾病负担[1]。尽管临床上开发了静脉溶栓(IVT)、机械取栓(EVT)和药物等方法干预缺血性卒中,但这些治疗手段因治疗窗口短、相对禁忌症多或引发感染出血等并发症,仅能给少数患者提供有效治疗,局限性大[2] [3]。因此,了解缺血性卒中的潜在病理机制,并从中寻找新的治疗手段尤为重要。

在哺乳动物基因组中,仅存在2%~5%的基因编码蛋白质,其余部分将近75%的基因组是非编码RNA。其中将由RNA polyII合成的长度超过200个核苷酸的称为长非编码RNA (LncRNA) [4]。绝大多数长链非编码RNA (LncRNA)作为一类不编码蛋白质的 RNA,在多种神经退行性疾病中发挥关键作用,其中对缺血性卒中的发展及预后有着重要影响。近来研究表明,LncRNAs在阿尔茨海默病、亨廷顿病和强直性脊柱炎等中枢神经退行性疾病表达被动态调控,通过多种转录和转录后等机制来调节蛋白质编码基因的表达,从而影响神经发生和CNS细胞稳态[5]。与这些退行性疾病类似,缺血性卒中导致小胶质细胞极化、血管内皮细胞生成和神经元凋亡等病理生理过程,间接破坏了脑微环境稳态。值得一提的是多种LncRNA如ANRIL、MEG3、H19等在此期间出现表达异常[6] [7]。因此,本文就LncRNAs在缺血性卒中发展中的作用机制及临床意义进行探讨。

2. LncRNA分类

最初根据它们与蛋白质编码基因相对的相对位置被分为几种不同的类型:(1) 正义LncRNAs;(2) 反义LncRNAs;(3) 内含子LncRNAs;(4) 基因间LncRNAs;(5) 双向LncRNAs;(6) 增强子LncRNAs。按照效应机制的不同,将长链非编码RNA四大类:(a) 信号分子;(b) 诱饵分子;(c) 引导分子;(d) 支架分子。

这里我们根据其功能对LncRNA作用机制进行分类探讨:

一、转录前调控:哺乳动物LncRNA介导的表观遗传学改变的研究,最早源于基因组印记和X染色体失活两个方面,分别与H19 [8] [9]和Xist RNA [10]密切相关。近十年研究发现,LncRNA与基因组调控密切相关,并且发现了更为具体的作用机理,如下:(i) 在编码蛋白的基因上游或启动子区转录,干扰下游基因的表达[11]。(ii) 抑制RNA聚合酶II或者介导染色质重构以及组蛋白修饰[12]。(iii) 与编码蛋白基因的转录本形成互补双链,干扰mRNA的剪切,形成不同的剪切形式[13]。(iv) 与编码蛋白基因的转录本形成互补双链,在Dicer酶的作用下产生内源性siRNA [14]等。

二、转录调控:1) 在编码蛋白的基因上游或启动子区转录,干扰下游基因的表达:酵母的SER3基因受到上游一段LncRNA——SRG1的干扰[15];人类细胞中的细胞周期蛋白D1 (CCND1)的表达,DNA损伤信号诱导该基因启动子上游一段LncRNA的表达,它可调节RNA结合蛋白——TLS的活性,接着TLS抑制CREB结合蛋白——组蛋白乙酰基转移酶和p300的活动,进而使CCND1基因的表达沉默[11]。2) 抑制RNA聚合酶II或者介导染色质重构以及组蛋白修饰,影响下游基因的表达:小鼠的一段LncRNA——Evf2转录自一段超保守的远端增强子,它可与转录因子DLX2形成转录复合体,并结合至另一个增强子上,从而诱导邻近蛋白编码基因DLX6的表达。通过与影响启动子选择的抑制性复合物相互作用,封锁启动子区域来调控RNA聚合酶(RNAP) II的活动从而干扰基因表达[16]

三、转录后调控:1) 与编码蛋白基因的转录本形成互补双链,干扰mRNA的剪切,形成不同的剪切形式,如LncRNA-Zeb2/Sip1能够和HOX位点转录的mRNA的一个内含子的5’端剪切位点形成双链,从而防止该内含子被剪切。该区域含有对于Zeb2蛋白表达所必须的核糖体结合位点,Zeb2通过这种方式能提高Zeb2蛋白的表达量[13]。2) 与编码蛋白基因的转录本形成互补双链,在Dicer酶的作用下产生内源性siRNA:LncRNA的复性(退火)具有靶向作用,使蛋白受体复合物能够识别正义链mRNA转录本,这一作用类似于RNA诱导的沉默复合物(RISC)通过siRNA靶向作用于mRNA,来自于互补转录本甚至是LncRNA的双链RNA,结合延长的内部发夹结构,能够被加工成内源性siRNA以使基因表达沉默[14]。3) 与特定蛋白质结合,LncRNA转录本可调节相应蛋白的活性:LncRNA——NKILA与NF-κB相互作用-IκBα复合物通过结合p65并调节T细胞活化诱导的细胞死亡是通过抑制NF-κB活性[17]。4) 作为结构组分与蛋白质形成核酸蛋白质复合体:Tsai等的研究显示,HOTAIR作为骨架分子发挥作用,其两端结合不同的组蛋白修饰复合体——5’端结合PRC2复合体,而3’端结合LSD1/CoREST/REST复合体,即由赖氨酸特异性脱甲基酶1 (Lysine-specificdemethylase 1, LSD1)、阻遏元件-1沉默转录因子辅阻遏物(Corepressor for repressor element-1 silencing transcription factor, CoREST)和阻元件-1沉默转录因子(Repressor element-1 silencing transcription factor, REST)等3种蛋白质结合而成的复合体[18]。5) 结合到特定蛋白质上,改变该蛋白质的细胞定位:与HuR相互作用,导入细胞质;与GRSF1相互作用以稳定线粒体[19]。6) 作为小分子RNA (如miRNA、piRNA)的前体分子:LncRNA Bic、H19分别可作为miR-155和miR-675的前体[20] [21]。7) LncRNA作为ceRNA,结合相应的miRNA使其不发挥作用,增加相关蛋白翻译和表达:螯合miR-205,从而导致上调ZEB1和ZEB2 mRNA并促进上皮–间质转化[22]

四、微肽(micropeptides):LncRNA具备一个或多个sORF (短开放阅读框),可编码功能性微肽(SEP)并参与到各种生物过程中,例如炎症与免疫、人类常见癌症等过程[23]。研究表明,一种由心肌球细胞(CDCs)分泌的微肽slitharin (Slt)在心肌梗死大鼠中发挥了心脏保护作用,表现为在损伤后48小时减少了梗死面积[24]。此外,LncRNA AF127577.4分泌的微肽通过METTL3抑制胶质母细胞瘤细胞增殖[25]

3. 不同LncRNA机制对缺血性卒中的调控

1) ANRIL——CARD8上游转录:Bai Ying的团队利用人脐静脉内皮细胞中ANRIL的敲除和过表达,验证得到CARD8是受其调控的下游靶基因。通过卒中病例风险基因的对照研究得知CARD8 SNPrs2043211与缺血性卒中存在显著基因型相关性。ANRIL可能通过相同的启动子序列调节CARD8通路来增加缺血性卒中的风险,但是CARD8在卒中中的详细发病机制尚不清楚[26]

2) FosDT——染色质修饰蛋白coREST和Sin3a:Suresh L等人[27]在成年大鼠MCAO/R模型中发现基因同源的FosDT和Fos表达被诱导增加,同时REST和coREST的mRNA及蛋白水平也被显著诱导。已知染色质修饰蛋白CMP——coREST和Sin3a作为REST复合物介导的基因抑制的重要组成部分,LncRNA可与CMP结合,引导它们到特定的基因组位点[28]。REST可抑制AMPA受体亚基GluR2启动子活性和基因表达,增加钙离子通过AMPA受体离子通道内流,加重神经元损伤从而促进缺血后神经元凋亡[29]。与此同时,RNA免疫共沉淀显示,在再灌注6小时后,coREST和Sin3a与FosDT的结合增加。因此我们推论卒中发生时FosDT通过与coREST和Sin3a结合后靶向定位于REST基因,诱导其表达增加,抑制神经元细胞GluR2来促进后脑损伤。

3) H19——乙酰组蛋白H3、H4:有人发现MCAO小鼠的血浆、白细胞和大脑的H19水平升高。往脑室内注射H19 siRNA可以减少MCAO梗死体积和脑水肿,降低脑组织和血浆中TNF-α和IL-1β水平,卒中后24 h后血浆IL-10浓度增加,减轻了梗塞后14天的神经损伤和功能缺陷。通过BV2细胞OGD实验进一步得知,敲低H19可减少TNFα和CD11b的产生,增加Arg-1和CD206的表达,驱动小胶质细胞从M1向M2极化。与此同时,他们发现H19可正向调控组蛋白去乙酰化酶1 (HDAC1)来影响乙酰组蛋白H3、H4的表达。因此推测H19可能通过间接影响组蛋白修饰驱动小胶质极化来影响缺血缺氧引起的神经炎症,其中H19调节HDAC1的具体机制有待明确[30]

4) H19——miR-675产物——p53蛋白:Wang J等人[31]利用H19 siRNA显著降低小鼠MCAO/R后14d脑梗死体积,促进小鼠神经缺陷恢复,且增加了Notch1蛋白水平、p53靶基因的转录及其激活形式p-p53的表达。而抑制p53可消除H19的这些原始影响。查阅相关资料得知[32],P53可作为Notch1转录的活性和负调控因子,被招募到Notch1基因的启动子来启动Notch1的转录。另外,有人报道过miR-675作为H19的成熟产物也可以抑制p53的活性[33]。因此,他们猜测,在缺血性脑卒中脑内表达上调的H19可作为miR-675的来源,可以减少p53蛋白,从而抑制Notch1及其下游通路,阻碍了神经发生。

5) ANRIL——结合NF-κB/IκB蛋白:Zhang Bo等人在糖尿病(DM)合并脑梗死(CI)后血管生成方面的研究中发现,DM + CI组中血管生长因子VEGF、NF-κB、p-IκB/IκB蛋白表达、VEGF、FLT-1、NF-κB和mRNA蛋白表达增加,并且在大鼠DM合并MCAO模型中,通过转染高表达ANRIL的质粒可以显著升高VEGF和NF-κB,这一效果被NF-κB抑制剂(PDTC)所阻遏。ANRIL的上调通过激活NF-κB信号通路上调VEGF表达,促进脑梗死的血管生成而起到机体保护作用。进一步得知,NKILA是与NF-kB/IκB结合,直接屏蔽IκB磷酸化基序,从而影响IκB磷酸化和NF-κB激活,进一步激活NF-κB信号通路[34] [35]

6) 内源性竞争结合miRNA:Wang Haoyue的团队发现在OGD处理后24 h,小胶质细胞中TUG1的细胞水平短暂升高,与下调的miR-145a-5p呈反相关,然后他们采用RNA-RNA pull-down证实TUG1与miR-145a-5p存在竞争性结合。进一步利用TUG1 siRNA转染BV-2细胞,然后进行OGD 4 h/复氧24 h,可减少了促炎细胞因子(TNF-α, IL-6)并增加抗炎细胞因子IL-10的释放,表明小胶质从M1向M2表型转化。同时,TUG1的敲除阻止了OGD诱导的NF-κB通路的激活,而miR-145a-5p抑制剂共转染却明显消除了TUG1敲低对NF-κB激活的影响。因此他们得出结论:TUG1可以竞争性结合miR145a-5p,增加NF-kB表达,导致小胶质向M1极化,加重神经炎症[36]。另外Dong You等人的研究也发现在脑卒中发生时,MEG3会导致脑血管细胞凋亡和神经元损伤,具体机制推测为LncRNA MEG3“sponge”MiR-378,减少GRB2诱导神经元自噬从而减少神经功能损伤[37]-[39]。类似地,Hongwei Wang等人的研究得到:敲低MALAT1增加了MA-C细胞的细胞生存能力,降低了细胞凋亡,最终证实是MALAT1通过竞争性结合miR-145积极调节AQP4的表达[40]

7) LncRNA-U90926——MDH2复合物:Chen Jian等人发现LncRNA-U90926在体内外缺血/再灌注暴露的小胶质细胞中均显著增加。另外,他们利用AAV介导小胶质细胞U90926沉默的技术,减少卒中小鼠脑内中性粒细胞向缺血性病变部位的浸润,减轻了神经功能缺损并减少了梗塞体积。通过对机制的深入挖掘,他们发现U90926可直接与苹果酸脱氢酶2 (MDH2)结合形成复合体,并竞争性地抑制MDH2与CXCL2 3’非翻译区(UTR)的结合,从而防止MDH2介导的CXCL2 mRNA衰变,而CXCL2配体正是作为中性粒细胞浸润所必需的[41]

4. 讨论与展望

综上所述,LncRNA可以通过对转录前后的分子调控来调节神经元细胞存活、小胶质细胞极化和血管内皮细胞发生,这些病理生理过程在缺血性卒中中发挥重要作用。LncRNA在缺血性脑卒中发生时可以通过多种机制途径,对卒中的转归产生或正面或负面或双向的影响(表1)。阐明这些LncRNA在正常和病理条件下的生物系统中的功能和机制,可能为识别生物标志物和新的治疗靶向提供潜在的机会。目前为止,在缺血性脑卒中病理过程中被研究的LncRNA还十分有限,研究最广泛的是LncRNA作为ceRNA分子参与相应miRNA的拮抗来调控下游蛋白表达[42]。然而,LncRNA编码微肽的机制在缺血性脑卒中方面是否存在相关作用通路还有待深入挖掘。这将为阐明缺血性卒中发展机制拓宽新的思路。有证据表明,HSC70是树突状细胞(DCs)中抗原运输和呈递所需的伴侣,而MIR155HG在炎症抗原呈递细胞中高度表达,其编码的P155通过破坏HSC70-HSP90机制调节主要组织相容性复合体ii类介导的抗原呈递和T细胞启动。外源性注射P155改善两种经典小鼠dc驱动的自身炎症模型。其中P155是通过与热休克同源蛋白70 (HSC70)的腺苷5’-三磷酸结合域(ATP酶区)相互作用,抑制HSC70的ATP酶活性,从而破坏其功能活动[43]。另外有研究显示同为热休克蛋白家族的HSP70在脑卒中方面存在多种保护性机制[44]。它们的ATP结合域存在高度的保守性,因此我们设想P155可能也会通过结合HSP70而抑制其功能,并可以采取共定位方式进行验证。同时,在临床研究脑卒中患者血清成分时,发现LncRNA MIR155HG上调,可以衍生mir-155,从而加重炎症,对脑卒中疾病发展产生不利影响[45] [46]。Bhatta等[47]在小鼠巨噬细胞中发现一种LncRNA 1810058I24Rik,它在暴露于脂多糖(lipopolysaccharide, LPS)以及其他Toll样受体(Toll-like receptors, TLR)和炎症细胞因子的人和鼠骨髓细胞中被下调。并且其编码的线粒体微肽-47 (mitochondrial micropeptide-47, Mm47)被证实可激活NLRP3炎性小体,参与机体的先天免疫反应和炎症进程。小胶质细胞作为脑内巨噬细胞,NLRP3炎症小体参与介导脑内巨噬细胞——小胶质细胞的极化过程以及血脑屏障的通透性[48] [49],从而影响脑卒中预后,Mm47或将成为治疗脑卒中新的靶点。

Table 1. lncRNAs在脑缺血损伤中的作用

1. Role of lncRNAs in cerebral ischemic injuries

LncRNA

作用机制

卒中相关

具体机制

预后影响(正/负面)

表观遗传

在编码蛋白的基因上游或启动子区转录

ANRIL

CARD8是ANRIL调控的下游靶基因。CARD8单核苷酸多态性rs2043211与缺血性脑卒中显著相关。ANRIL可能通过调节CARD8通路增加缺血性卒中的风险

负面:增加卒中风险

与编码蛋白基因的转录本形成互补双链,在Dicer酶的作用下产生内源性siRNA

未知

/

/

抑制RNA聚合酶II或者介导染色质重构以及组蛋白修饰

FosDT

与(CMPs) Sin3a和coREST的结合, 调控下游基因

负面:梗死增加,运动缺陷

H19

乙酰组蛋白H3和乙酰组蛋白H4下调

负面:M1极化上调炎症

与编码蛋白基因的转录本形成互补双链,干扰mRNA的剪切,形成不同的剪切形式

未知

/

/

非表观遗传

与特定蛋白质结合,LncRNA转录本可调节相应蛋白的活性

NKILA

与NF-kB/IκB结合,影响IκB磷酸化和 NF-κB激活,上调VEGF表达

正面:血管再生

作为小分子RNA (如miRNA、piRNA)的前体分子

H19

作为miR-675前体,抑制p53的活性

负面:梗死增加,神经功能缺陷上调炎症,促进凋亡

LncRNA作为ceRNA,竞争性结合相应的miRNA使其不发挥作用,增加相关蛋白翻译和表达

TUG1

miR-145-a-5p的相互作用,激活NF-κB

负面:M1极化上调炎症

MEG3

MEG3/MiR-378/GRB2轴减少神经元自噬

负面:神经元凋亡增加减轻细胞凋亡、脑梗死和神经元损失,从而保护神经元

Malat1

竞争性结合miR-145积极调节AQP4的表达或者

负面:星形胶质细胞凋亡增加,存活率下降上调炎症

作为结构组分与蛋白质形成核酸蛋白质复合体

LncRNA-U90926

U90926与MDH2结合,并竞争性地抑制其与CXCL2 3’-UTR的结合,防止CXCL2 mRNA的衰变

负面:促进中性粒细胞浸润加重缺血性脑损伤

结合到特定蛋白质上,改变该蛋白质的细胞定位

未知

/

/

NOTES

*通讯作者。

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