郑刚教授：非编码基因组在心血管疾病中的临床意义（上篇）_非编码基因组_心血管疾病

郑刚教授：非编码基因组在心血管疾病中的临床意义（上篇）

2024-10-09 来源：医脉通

关键词：非编码基因组心血管疾病

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郑刚

23篇内容

北京时间10月7日，2024年诺贝尔生理学或医学奖率先公布。瑞典卡罗琳医学院宣布，将2024年诺贝尔生理学或医学奖授予科学家维克托·安布罗斯（Victor Ambros）和加里·鲁夫昆（Gary Ruvkun），因他们发现微小RNA（miRNA）及其在转录后基因调控中的作用。miRNA是一类常见的非编码RNA（ncRNA），它本身不编码蛋白质，但能够靶向结合mRNA从而通过转录后基因沉默来调控基因表达。那么，在心血管疾病的发生发展过程中，非编码基因组有哪些临床意义？来自泰达国际心血管病医院的郑刚教授根据最新发表的文章进行了汇总。

作者：郑刚泰达国际心血管病医院

本文为作者授权医脉通发布，未经授权请勿转载。

PART.01 非编码基因组与心血管疾病相关性

ncRNA在临床应用中具有重要意义，可分为多种类别，包括微小RNA（miRNA）、长非编码RNA（lncRNA）和环状RNA（circRNA）^[9]。小干扰RNA（siRNA）可用于靶向ncRNA。RNA干扰（RNAi）介导的siRNA具有高度适应性，用于沉默其信使RNA（mRNA）的蛋白质编码基因。miRNA是22个核苷酸的RNA分子，通过改变翻译过程来调节细胞信号传导和下调特定基因的表达^[10]。

通过使用各种工具和技术对心血管疾病中临床相关的ncRNA进行分类^[11-14]。研究显示ncRNA存在与心肌梗死、冠状动脉疾病、心力衰竭和肺动脉高压相关^[11-14]。大多数循环中miRNA来源于血细胞，其他来源于各种组织，如心脏^[12-15]。lncRNA在心血管疾病中的调节及其临床意义在ACS和心肌（miR-1，miR-133a，miR-208a，miR-208b，miR-499p）、动脉硬化（miR-33a，miR-122，miR-126，miR-1，micro-121/222）、心肌肥大（miR-208a，miR-19a/b，miR-155，miR-199a，miR-1、miR-101，miR-185，miR-34a，miR-145，miR-150，miR-178，miR320a，miR-425b）和心力衰竭（miR-320a, miR-4235p, miR-4235p, miR-200b, miR-4235p,miR-4235p, miR-4235p, miR-200b, miR-200b, miR-622, miR-1228, miR-200b, miR-200b,miR-499, miR-499, miR-223, miR-499, miR-200b, miR-499, miR-223, miR-1306, miR-18a,miR-26b, miR-27a, miR-26b, miR-26b, miR-26b）。miR-17-92簇成员、炎症相关的miR-155和平滑肌富集的miR-145在冠心病患者中的水平降低^[15-55]。相反，心肌富集的miRNA（miR-133a、miR-208a）在冠心病患者中往往更高^[56-30]。

还有其他证据表明，心脏风险因素会影响血液中miRNA水平。研究表明，患有糖尿病患者的miR-20b、miR-21、miR-24、miR-15a、miR-126、miR-191、miR-197、miR-223、miR-320和miR-486水平显著降低，但miR-28-3p水平适度增加。在单变量和多变量分析中，822名患者中确认了29个miR-126数据点^[61-70]。在糖尿病患者中，miR-126的减少仅限于血浆中的循环小泡^[71-74]。人类circRNA0037911、circRNA0126991和circRNA0005870似乎是高血压生物标志物的最佳候选者。circRNA 0037911和0126991在高血压患者的血液中被发现高度调节，而circRNA0005870被下调。总之，这些circRNAs似乎参与了血管内皮功能障碍，从而导致动脉高血压的发展^[7-10]。CircRNAs参与心脏肥大（CircHRCR、CircSLc8a1和Circ-0000203）、心肌梗死（CircNFIB、CircHIPK3和CircRNA10567）、心脏肥大（CircHRCR、CircSLc8al和Circ-00000203）、动脉硬化（CircANRIL、Circ-0003204、CircWDR77、CircTCF25）和冠心病（CircZNF609、CircRp6、CircNrg1和CircTCF2）^[11-15]。目前的研究仍处于起步阶段，miRNA、lncRNA和circRNA的分类及其调控机制和功能尚不清楚^[11]。因此，最近的研究清楚地基于RNA的不寻常结构建立了本质上新颖的治疗靶点，以应对当前心血管疾病的挑战^[12]。到目前为止，只有少量的非编码蛋白转录物被鉴定和探索用于心血管疾病的临床应用。目前有各种主要的ncRNA治疗方法正在酝酿中 ^[12]。

PART.02 miRNA和心血管疾病

miRNA lin-4于1993年在秀丽隐杆线虫中被鉴定^[71]。miRNA的合成发生在细胞核中，并由RNA聚合酶II转录为编码和非编码的多腺苷酸化的pri-miRNA。pri-miRNA产生发夹状结构，并由Drosha核酶活化，然后转运到细胞质^[12]。DICER去除pri-miRNA的末端环，产生20-25核苷酸碱基对的dsRNA复合物。dsRNA附着在miRNA连接的RISC（RNA诱导的沉默复合物）上，靶向mRNA，导致mRNA去腺苷化和翻译抑制^[13]。体内和体外研究表明，miRNA在心血管疾病如心肌肥大、心力衰竭、心律失常、ACS、心肌梗死、动脉硬化、风湿性心脏病和肺动脉高压的调节中起着关键作用^[14]。心肌肥大（MH）是由心血管疾病的发展引起的，包括心脏瓣膜狭窄和高血压，并导致心力衰竭和死亡^[75]。几种miRNA，包括miR-208a、miR-19a/b、miR-34a、miR-145、miR-150、miR-378等，参与MH的发展^[76]。MiR-378是一种抗MH miRNA，调节胰岛素样生长因子受体（Igf1r）、生长因子受体结合蛋白2（Grb2）和Ras激酶抑制剂1（Ksr1）^[77]。MiR-185调节心脏细胞增殖，并与信号转导机制有关。MiR-34a调节参与自噬的Agt9a基因。转录激活因子p300受miR-150的调节^[78]。MiR-1通过降低GATA结合蛋白4（GATA4）和钙调蛋白Mef2a的表达参与心肌细胞的生长发育，后者调节钙信号通路和蛋白表达，可作为诊断和治疗的靶点^[79]。

2.1 miRNA和心力衰竭

心力衰竭是由心脏调节机制的失败引起的[80]。许多不同形式的miRNA，如miR-320a、miR-423-5p、miR-200b、miR-622、miR-1228、miR-208b、miR-499、miR-223、miR-1254、miR-1306、miR-18a、miR-26b、miR-27a、miR-30e、miR-106a、miR-199a，在心力衰竭条件的发展中至关重要^[81]。左心室早期肥大发生可能由miR-125b引起并导致心力衰竭。脑钠肽（BNP）的表达受miR-200b、miR-622和miR-1228的调节。心力衰竭也可能是由miR-208b和miR-499的表达增加引起的。心力衰竭中的这些miRNA调节可作为诊断和治疗方法的靶点^[82]。

2.2. 心律失常

主要由心肌离子通道失衡和传导失调引起。心房颤动是在心血管疾病中观察到的一种严重AR，可导致心力衰竭、卒中和死亡^[83]。有各种类型的miRNA参与心血管疾病患者AR的发展，包括miR-664、miR-133、miR590、miR-130a、miR-21、miR-208b、miR-483、miR-1和miR-150。此外，房颤由miRNAs miR-328、miR-2、miR-664、miR-483、miR-133、miR-1、miR-208b、miR-590、miR-328和miR-223控制^[84]。miR-130a的过度表达与蛋白连接蛋白（43cx43）有关。MiR-150调节房颤患者的血小板计数，在纤维化和炎症中起主要作用，并参与房颤的发展^[85]。

2.3. miRNA与ACS和心肌梗死

ACS是由心脏血流量减少、冠状动脉立即堵塞和局部心脏坏死引起的，所有这些都有助于急性心肌梗死（AMI）的发展^[86]。AMI患者具有高水平的miR-1表达。已经发现AMI患者的MiR-1、MiR-133a和MiR-208a水平较高。冠状动脉搭桥术患者的心脏骤停受miR-208b和miR-499-5p的调节^[87]。这两种miRNA由失调的心肌表达。AMI患者的表达水平降低。这些miRNA调控相关的表达谱可用于早期诊断和治疗^[88]。在患有AMI的小鼠模型中已经观察到高miR-208表达水平。AMI患者miRNA表达的高通量分析可以进一步探索，用于敏感和特异的早期诊断和治疗^[89]。

2.4 miRNA与动脉粥样硬化（AS）

miRNA通过血管新生、内皮功能障碍、脂质积聚、局部炎症、钙化、血栓形成和内皮功能障碍在动脉粥样硬化的发生中发挥重要作用^[90]。在冠心病的发展中发挥着重要作用，在全球范围内导致重大死亡。miRNA的表达谱已在动脉硬化患者中进行了研究。MiR-33通过涉及炎症反应、细胞周期进展、脂质代谢和增殖来调节动脉硬化疾病进展^[91]。在动脉硬化患者中，miR-122大量表达。

MiR-122控制高密度脂蛋白（HDL）和低密度脂蛋白（LDL）的水平。内皮细胞上的白细胞聚集由miR-126介导的血管细胞黏附分子-1（VCAM-1）上调触发^[92]。Mi-R1调节肌球蛋白轻链激酶（MLCK）和细胞外信号调节激酶（ERK）的信号通路。MiR-221和MiR-222控制血管平滑肌细胞（VSMCs）的生长和发育。在动脉硬化患者中，miR-126、miR-1和miR-221/222的表达通常较少^[93]。

2.5 miRNA和风湿性心脏病

风湿性心脏病病变主要在二尖瓣中发现，风湿性心脏病组织和血浆样品具有显著水平的miRNA-1299和miRNA-1183表达。MiR-328-3p在风湿性心脏病和房颤患者中发现^[94]。已经发现在风湿性心脏病患者中MiRNA-432的表达水平较低。所有这些微小RNA都可以用于早期诊断。需要进一步的研究来了解更多关于风湿性心脏病中miRNA调节的信息^[95]。

2.6 lncRNA和心血管疾病

与调节基因表达的miRNA相比，lncRNA在本质上更复杂和异质。lncRNA参与心血管疾病，并根据其结构和功能分为不同的类别，包括双向lncRNA、增强子LncRNAs、正义lncRNA、反义lncRNA、基因间lncRNA和内含子lncRNA^[96]。lncRNA与DNA、RNA、蛋白质、染色质修饰复合体的元件和转录因子的相互作用改变了基因表达水平。引导的lncRNA可以激活lncRNA过程，也可以通过离域调节元件抑制基因表达^[97-99]。核糖核蛋白（RNP）复合物的形成涉及支架lncRNA。lncRNA作为初级miRNA前体，其被转化为成熟miRNA，而miRNA前质被抑制。当lncRNA激活基因组调控区的转录时，长程基因调控开始。lncRNA与miRNA相互作用并破坏RNA分子的调节系统^[97]。lncRNA也作为母体或父亲的基因组印迹表达，有助于生物体的发育^[100-101]。

各种类型的细胞、血管系统和血管的整合都参与了心脏的生成^[98]。lncRNA，也称为超级增强子lncRNA（SE lncRNA），控制组织和细胞水平的转录。MyoD是一种重要的转录因子，与其他核心转录因子一起参与肌肉细胞分化^[99]。核心增强子元件（CE）由CERNA产生，它起到正反馈调节器的作用。最近观察到，各种类型的lncRNA参与心血管疾病的发展，包括CHRF、Myh7、LIPCAR、MIAT、Carl、LIPCRA、ASB9P1、RP11-218 M11.6、G078882、G064270、G000678、G030563、H19、TUG1、PFL、MIAT，AK081284、HOXA11 ASz、NRON和GAS5^[96]。H19在胚胎发生和心血管疾病期间表达，但在出生后被抑制。miRNA-675在心肌肥大中起负调控作用。miR-675-3p和miR-675-5p在心肌肥大中上调^[100]。一些促肥大因子也参与心肌肥大，并由Ca/钙调蛋白依赖性蛋白激酶II（CaMKII）介导。lncRNA-miRNA-mRNA轴可能是治疗方法的潜在靶点^[101]。所有这些研究都证实了lncRNA在心血管生物学和疾病中发挥着重要作用^[102]。

PART.03 lncRNAs在心血管疾病中的临床意义

3.1 高血压

有不同种类的lncRNA控制血管张力以控制高血压的病理生理学。LncRNAs贡献者高血压控制VSMC功能障碍，而控制lnc-Ang362的miRNAs 221和222控制VSMC的生长^[158-159]。

lncRNA NR_027032、NR_034083和NR_104181作为高血压疾病诊断的生物标志物。暴露于肽激素（血管紧张素II）的大鼠中lncRNA的差异表达具有多种功能，包括炎症、纤维化、血管收缩和肥大/增生[140]。lnc-Ang362的沉默降低了miRNA的表达，从而导致VSMC增殖的减少。生长停滞特异性5（lncRNA GAS5）调节高血压患者的血管重塑，主要在内皮细胞和血管平滑肌细胞中表达^[160]。VSMC lncRNAs NR4A3和AK098656的增殖诱导氧化应激诱导的VSMC增殖。CDKN2B-AS1反义lncRNA对高血压发育的易感性^[161]。

3.2 冠心病

心血管疾病中的斑块形成是由慢性炎症过程引起的，该过程使血管变窄并减少血流量，导致动脉粥样硬化和局部缺血，从而导致冠心病的发展^[162]。各种lncRNA与冠心病的病理生理学有关，并作为生物标志物，包括MIAT、MALAT1、ANRIL、LIPCAR、MALAT2、MIAT和SMILR。HOTTIP，一种lincRNA-p21，调节细胞增殖和凋亡^[163]。lncRNA BANCR与miRNA表达的胆固醇稳态调节因子（CHROME）相关。lncRNA NEXN-AS1参与减轻动脉粥样硬化。所有这些RNA都可能是诊断和治疗发展的靶点^[164]。

3.3 急性心肌梗死

AMI是由血流阻塞、血液中氧气不足和代谢紊乱引起的。有多种lncRNA参与AMI的潜在信号传导^[165]。在大鼠模型中，lncRNA MIAT参与心肌变性并调节不利的心脏重塑^[165]。H19参与自噬，HOTIAR参与心脏保护活性并与miRNA结合，KCNQ1OT1参与左心室功能障碍，MALAT1调节心肌细胞，MDRL参与线粒体功能障碍，MEG3和MEG3参与心肌细胞凋亡，MIAT调节心肌肥大，Mirt1/2调节心脏重塑^[102]，NORATT021972调节心脏活动，PCFL调节心脏纤维。所有这些lncRNA在病理条件、诊断和治疗的调节中都显示出重要意义。

3.4 心力衰竭

在慢性疾病中，心脏不能正确地泵送收缩压和舒张压，这可能会增加呼吸急促、疲劳、炎症和心跳加快^[166]。有多种lncRNA参与心力衰竭，包括lncRNA MHRT、CHAER、CHRF、APF、CARL、aHIF、MIAT和CHAST^[167]。MHRT是一簇特定的RNA，在维持心脏的生理条件方面发挥着重要作用。在心力衰竭条件下观察到MHRT的表达减少，MHRT、Myh6和Myh7的亚型参与心力衰竭^[144]。在心脏应激反应过程中，Brg1调节从肌球蛋白到肌球蛋白重链的稳态。CHRF的过度表达诱导病理过程并诱导细胞凋亡。lncRNA CHAER参与心脏重塑，并在小鼠心脏心力衰竭期间表达^[147]。lncRNA PCR2在动物模型中显示出心脏保护特性。APF调节自噬，CARL调节血管生成，aHIF调节细胞凋亡，MIAT调节心肌梗死中的心脏纤维化过程^[145]。高血压中的血管重塑受GAS5和AK0986656 lncRNA的调节。正在研究的所有这些lncRNA的研究可能是心力衰竭前诊断和治疗的主要靶点 ^[145]。

（待续下篇）

专家简介

微信图片_20241009134557.jpg

郑刚教授

现任泰达国际心血管病医院特聘专家，济兴医院副院长

中国高血压联盟理事，中国心力衰竭学会委员，中国老年医学会高血压分会天津工作组副组长、中国医疗保健国际交流促进会高血压分会委员。

天津医学会心血管病专业委员会委员，天津医学会老年病专业委员会常委。天津市医师协会高血压专业委员会常委，天津市医师协会老年病专业委员会委员，天津市医师协会心力衰竭专业委员，天津市医师协会心血管内科医师分会双心专业委员会委员。天津市心脏学会理事、天津市心律学会第一届委员会委员，天津市房颤中心联盟常委。天津市医药学专家协会第一届心血管专业委员会委员，天津市药理学会临床心血管药理专业委员会常委。天津市中西医结合学会心血管疾病专业委员会常委

《中华老年心脑血管病杂志》编委，《中华临床医师杂志》（电子版）特邀审稿专家，《中华诊断学电子杂志》审稿专家，《华夏医学》杂志副主编，《中国心血管杂志》常务编委，《中国心血管病研究》杂志第四届编委，《世界临床药物》杂志编委、《医学综述》杂志会编委、《中国医药导报》杂志编委、《中国现代医生》杂志编委、《心血管外科杂志（电子版）》审稿专家

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