en
×

分享给微信好友或者朋友圈

使用微信“扫一扫”功能。
通讯作者:

陆齐,E⁃mail:luqint@sima.com

中图分类号:R54

文献标识码:A

文章编号:1007-4368(2021)10-1552-07

DOI:10.7655/NYDXBNS20211025

参考文献 1
TRIPOSKIADIS F,XANTHOPOULOS A,BUTLER J.Cardiovascular aging and heart failure:JACC review top⁃ ic of the week[J].J Am Coll Cardiol,2019,74(6):804-813
参考文献 2
BENJAMIN E J,BLAHA M J,CHIUVE S E,et al.Heart disease and stroke statistics ⁃ 2017 update:a report from the American Heart Association[J].Circulation,2017,135(10):e146-e603
参考文献 3
KAIKKONEN M U,ADELMAN K.Emerging roles of non⁃ coding RNA transcription[J].Trends Biochem Sci,2018,43(9):654-667
参考文献 4
ANASTASIADOU E,JACOB L S,SLACK F J.Non ⁃cod⁃ ing RNA networks in cancer[J].Nat Rev Cancer,2018,18(1):5-18
参考文献 5
LIU S,YANG Y,JIANG S,et al.Understanding the role of non⁃coding RNA(ncRNA)in stent restenosis[J].Ath⁃ erosclerosis,2018,272:153-161
参考文献 6
SALLAM T,SANDHU J,TONTONOZ P.Long noncoding RNA discovery in cardiovascular disease:decoding form to function[J].Circ Res,2018,122(1):155-166
参考文献 7
ZHANG Y,DU W,YANG B.Long non ⁃coding RNAs as new regulators of cardiac electrophysiology and arrhyth⁃ mias:molecular mechanisms,therapeutic implications and challenges[J].Pharmacol Ther,2019,203:107389
参考文献 8
CARRIERI C,CIMATTI L,BIAGIOLI M,et al.Long non⁃ coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat[J].Nature,2012,491(7424):454-457
参考文献 9
SALMENA L,POLISENO L,TAY Y,et al.A CeRNA hy⁃ pothesis:the Rosetta stone of a hidden RNA language?[J].Cell,2011,146(3):353-358
参考文献 10
DYKES I M,EMANUELI C.Transcriptional and post ⁃ transcriptional gene regulation by long non ⁃ coding RNA [J].Genomics Proteomics Bioinformatics,2017,15(3):177-186
参考文献 11
JÉGU T,AEBY E,LEE J T.The X chromosome in space [J].Nat Rev Genet,2017,18(6):377-389
参考文献 12
WANG F,CHAINANI P,WHITE T,et al.Deep learning identifies genome⁃wide DNA binding sites of long noncod⁃ ing RNAs[J].RNA Biol,2018,15(12):1468-1476
参考文献 13
ENGREITZ J M,HAINES J E,PEREZ E M,et al.Local regulation of gene expression by lncRNA promoters,tran⁃ scription and splicing[J].Nature,2016,539(7629):452-455
参考文献 14
BARWARI T,JOSHI A,MAYR M.MicroRNAs in cardio⁃ vascular disease[J].J Am Coll Cardiol,2016,68(23):2577-2584
参考文献 15
孟荔,史爱武.微小RNA在心血管疾病中的研究进展[J].南京医科大学学报(自然科学版),2018,38(4):562-568
参考文献 16
BALLANTYNE M D,MCDONALD R A,BAKER A H.ln⁃ cRNA/MicroRNA interactions in the vasculature[J].Clin Pharmacol Ther,2016,99(5):494-501
参考文献 17
LIANG H,ZHANG J,ZEN K,et al.Nuclear microRNAs and their unconventional role in regulating non ⁃ coding RNAs[J].Protein Cell,2013,4(5):325-330
参考文献 18
EBERT M S,NEILSON J R,SHARP P A.MicroRNA sponges:competitive inhibitors of small RNAs in mamma⁃ lian cells[J].Nat Methods,2007,4(9):721-726
参考文献 19
QU J,LI M,ZHONG W,et al.Competing endogenous RNA in cancer:a new pattern of gene expression regula⁃ tion[J].Int J Clin Exp Med,2015,8(10):17110-17116
参考文献 20
WANG F,YANG H,DENG Z,et al.HOX antisense lin⁃ cRNA HOXA⁃AS2 promotes tumorigenesis of hepatocellu⁃ lar carcinoma[J].Cell Physiol Biochem,2016,40(1/2):287-296
参考文献 21
XU S,KAMATO D,LITTLE P J,et al.Targeting epi⁃ genetics and non ⁃ coding RNAs in atherosclerosis:from mechanisms to therapeutics[J].Pharmacol Ther,2019,196:15-43
参考文献 22
GIMBRONE M A,GARCÍA ⁃ CARDEÑA G.Endothelial cell dysfunction and the pathobiology of atherosclerosis [J].Circ Res,2016,118(4):620-636
参考文献 23
BASATEMUR G L,JØRGENSEN H F,CLARKE M C H,et al.Vascular smooth muscle cells in atherosclerosis[J].Nat Rev Cardiol,2019,16(12):727-744
参考文献 24
BOON R A,JAÉ N,HOLDT L,et al.Long noncoding RNAs:from clinical genetics to therapeutic targets?[J].J Am Coll Cardiol,2016,67(10):1214-1226
参考文献 25
THUM T,CONDORELLI G.Long noncoding RNAs and microRNAs in cardiovascular pathophysiology[J].Circ Res,2015,116(4):751-762
参考文献 26
STEINBERG D,WITZTUM J L.Oxidized low ⁃density li⁃ poprotein and atherosclerosis[J].Arterioscler Thromb Vasc Biol,2010,30(12):2311-2316
参考文献 27
LI S,SUN Y,ZHONG L,et al.The suppression of ox⁃LDL⁃ induced inflammatory cytokine release and apoptosis of HCAECs by long non⁃coding RNA⁃MALAT1 via regulat⁃ ing microRNA ⁃155/SOCS1 pathway[J].Nutr Metab Car⁃ diovasc Dis,2018,28(11):1175-1187
参考文献 28
LI M N,QIAN M,KYLER K,et al.Endothelial⁃vascular smooth muscle cells interactions in atherosclerosis[J].Front Cardiovasc Med,2018,5:151
参考文献 29
CAI T,CUI X,ZHANG K,et al.LncRNA TNK2⁃AS1 regu⁃ lated ox⁃LDL⁃stimulated HASMC proliferation and migra⁃ tion via modulating VEGFA and FGF1 expression by sponging miR⁃150⁃5p[J].J Cell Mol Med,2019,23(11):7289-7298
参考文献 30
LIN Y,TIAN G,ZHANG H,et al.Long non⁃coding RNA SNHG16 regulates human aortic smooth muscle cell pro⁃ liferation and migration via sponging miR⁃205 and modu⁃ lating Smad2[J].J Cell Mol Med,2019,23(10):6919-6929
参考文献 31
HU X,MA R,FU W,et al.LncRNA UCA1 sponges miR⁃ 206 to exacerbate oxidative stress and apoptosis induced by ox ⁃ LDL in human macrophages[J].J Cell Physiol,2019,234(8):14154-14160
参考文献 32
LU Q,MENG Q,QI M,et al.Shear ⁃ sensitive lncRNA AF1312171 inhibits inflammation in HUVECs via regula⁃ tion of KLF4[J].Hypertension,2019,73(5):e25-e34
参考文献 33
ANDERSON J L,MORROW D A.Acute myocardial in⁃ farction[J].N Engl J Med,2017,376(21):2053-2064
参考文献 34
SONG X,SHAN D,CHEN J,et al.miRNAs and lncRNAs in vascular injury and remodeling[J].Sci China Life Sci,2014,57(8):826-835
参考文献 35
SHU L,ZHANG W,HUANG C,et al.lncRNA ANRIL protects H9c2 cells against hypoxia ⁃ induced injury through targeting the miR ⁃ 7 ⁃ 5p/SIRT1 axis[J].J Cell Physiol,2020,235(2):1175-1183
参考文献 36
LUO H,WANG J,LIU D,et al.The lncRNA H19/miR ⁃ 675 axis regulates myocardial ischemic and reperfusion injury by targeting PPARα[J].Mol Immunol,2019,105:46-54
参考文献 37
HAUSENLOY D J,YELLON D M.Myocardial ischemia⁃ reperfusion injury:a neglected therapeutic target[J].J Clin Invest,2013,123(1):92-100
参考文献 38
XUAN F,JIAN J,LIN X,et al.17⁃methoxyl⁃7⁃hydroxy⁃ benzene ⁃furanchalcone ameliorates myocardial ischemia/reperfusion injury in rat by inhibiting apoptosis and au⁃ tophagy via the PI3K ⁃Akt signal pathway[J].Cardiovasc Toxicol,2017,17(1):79-87
参考文献 39
GIAMPIERI F,AFRIN S,FORBES ⁃HERNANDEZ T Y,et al.Autophagy in human health and disease:novel ther⁃ apeutic opportunities[J].Antioxid Redox Signal,2019,30(4):577-634
参考文献 40
TANEIKE M,YAMAGUCHI O,NAKAI A,et al.Inhibi⁃ tion of autophagy in the heart induces age⁃related cardio⁃ myopathy[J].Autophagy,2010,6(5):600-606
参考文献 41
LIANG H,SU X,WU Q,et al.LncRNA 2810403D21Rik/Mirf promotes ischemic myocardial injury by regulating autophagy through targeting Mir26a[J].Autophagy,2020,16(6):1077-1091
参考文献 42
TANAKA Y,GUHDE G,SUTER A,et al.Accumulation of autophagic vacuoles and cardiomyopathy in LAMP ⁃ 2⁃ deficient mice[J].Nature,2000,406(6798):902-906
参考文献 43
WANG K,LIU C Y,ZHOU L Y,et al.APF lncRNA regu⁃ lates autophagy and myocardial infarction by targeting miR⁃188⁃3p[J].Nat Commun,2015,6:6779
参考文献 44
ZHU Z,ZHAO C.WITHDRAWN:LncRNA AK139128 promotes cardiomyocyte autophagy and apoptosis in myo⁃ cardial hypoxia ⁃ reoxygenation injury[J].Life Sci,2019:116705
参考文献 45
ZHANG Y,HOU Y M,GAO F,et al.lncRNA GAS5 regu⁃ lates myocardial infarction by targeting the miR ⁃525⁃5p/CALM2 axis[J].J Cell Biochem,2019,120(11):18678-18688
参考文献 46
LAI Y,HE S,MA L,et al.HOTAIR functions as a com⁃ peting endogenous RNA to regulate PTEN expression by inhibiting miR ⁃ 19 in cardiac hypertrophy[J].Mol Cell Biochem,2017,432(1/2):179-187
参考文献 47
ZHANG Q,WANG F,WANG F,et al.Long noncoding RNA MAGI1⁃IT1 regulates cardiac hypertrophy by modu⁃ lating miR ⁃ 302e/DKK1/Wnt/beta ⁃ catenin signaling path⁃ way[J].J Cell Physiol,2020,235(1):245-253
参考文献 48
LI Y,WANG J,SUN L,et al.LncRNA myocardial infarc⁃ tion ⁃ associated transcript(MIAT)contributed to cardiac hypertrophy by regulating TLR4 via miR ⁃ 93[J].Eur J Pharmacol,2018,818:508-517
参考文献 49
YUAN Y,WANG J,CHEN Q,et al.Long non ⁃ coding RNA cytoskeleton regulator RNA(CYTOR)modulates pathological cardiac hypertrophy through miR⁃155⁃medi⁃ ated IKKi signaling[J].Biochim Biophys Acta Mol Basis Dis,2019,1865(6):1421-1427
参考文献 50
JIA G,WHALEY ⁃CONNELL A,SOWERS J R.Diabetic cardiomyopathy:a hyperglycaemia⁃ and insulin⁃resistance⁃ induced heart disease[J].Diabetologia,2018,61(1):21-28
参考文献 51
BUGGER H,ABEL E D.Molecular mechanisms of diabet⁃ ic cardiomyopathy[J].Diabetologia,2014,57(4):660-671
参考文献 52
FENG Y,XU W,ZHANG W,et al.LncRNA DCRF regu⁃ lates cardiomyocyte autophagy by targeting miR⁃551b⁃5p in diabetic cardiomyopathy[J].Theranostics,2019,9(15):4558-4566
参考文献 53
ZHOU X,ZHANG W,JIN M,et al.lncRNA MIAT func⁃ tions as a competing endogenous RNA to upregulate DAPK2 by sponging miR⁃22⁃3p in diabetic cardiomyopa⁃ thy[J].Cell Death Dis,2017,8(7):e2929
参考文献 54
PICCOLI M T,GUPTA S K,VIERECK J,et al.Inhibition of the cardiac fibroblast⁃enriched lncRNA Meg3 prevents cardiac fibrosis and diastolic dysfunction[J].Circ Res,2017,121(5):575-583
参考文献 55
CHEN Y,ZHANG Z,ZHU D,et al.Long non⁃coding RNA MEG3 serves as a ceRNA for microRNA ⁃ 145 to induce apoptosis of AC16 cardiomyocytes under high glucose condition[J].Biosci Rep,2019,39(6):BSR20190444
参考文献 56
ZIMETBAUM P.Atrial fibrillation[J].Ann Intern Med,2017,166(5):ITC33-ITC48
参考文献 57
LI Z,WANG X,WANG W,et al.Altered long non⁃coding RNA expression profile in rabbit atria with atrial fibrilla⁃ tion:TCONS00075467 modulates atrial electrical remodeling by sponging miR ⁃ 328 to regulate CACNA1C[J].J Mol Cell Cardiol,2017,108:73-85
参考文献 58
LI X,DAI Y,YAN S,et al.Down ⁃ regulation of lncRNA KCNQ1OT1 protects against myocardial ischemia/reperfu⁃ sion injury following acute myocardial infarction[J].Bio⁃ chem Biophys Res Commun,2017,491(4):1026-1033
参考文献 59
LI M,WANG Y F,YANG X C,et al.Circulating long non⁃ coding RNA LIPCAR acts as a novel biomarker in pa⁃ tients with ST ⁃ segment elevation myocardial infarction [J].Med Sci Monit,2018,24:5064-5070
参考文献 60
SHEN C,KONG B,LIU Y,et al.YY1 ⁃induced upregula⁃ tion of lncRNA KCNQ1OT1 regulates angiotensin Ⅱ⁃in⁃ duced atrial fibrillation by modulating miR ⁃ 384b/CAC⁃ NA1C axis[J].Biochem Biophys Res Commun,2018,505(1):134-140
参考文献 61
CAO F,LI Z,DING W M,et al.LncRNA PVT1 regulates atrial fibrosis via miR⁃128⁃3p⁃SP1⁃TGF⁃β1⁃Smad axis in atrial fibrillation[J].Mol Med,2019,25(1):7
参考文献 62
GUO J,JIA F,JIANG Y,et al.Potential role of MG53 in the regulation of transforming ⁃growth ⁃factor ⁃β1⁃induced atrial fibrosis and vulnerability to atrial fibrillation[J].Exp Cell Res,2018,362(2):436-443
参考文献 63
BONOW R O,LEON M B,DOSHI D,et al.Management strategies and future challenges for aortic valve disease [J].Lancet,2016,387(10025):1312-1323
参考文献 64
YUTZEY K E,DEMER L L,BODY S C,et al.Calcific aortic valve disease:a consensus summary from the alli⁃ ance of investigators on calcific aortic valve disease[J].Arterioscler Thromb Vasc Biol,2014,34(11):2387-2393
参考文献 65
YU C,LI L,XIE F,et al.LncRNA TUG1 sponges miR ⁃ 204 ⁃ 5p to promote osteoblast differentiation through up⁃ regulating Runx2 in aortic valve calcification[J].Cardio⁃ vasc Res,2018,114(1):168-179
参考文献 66
XIAO X,ZHOU T,GUO S,et al.LncRNA MALAT1 sponges miR ⁃204 to promote osteoblast differentiation of human aortic valve interstitial cells through up⁃regulating Smad4[J].Int J Cardiol,2017,243:404-412
参考文献 67
HE W,LI F,ZHANG S,et al.LncRNA AFAP1⁃AS1 pro⁃ motes osteoblast differentiation of human aortic valve in⁃ terstitial cells through regulating miR ⁃ 155/SMAD5 axis [J].Mol Cell Probes,2020,50:101509
目录contents

    摘要

    长链非编码RNA(long noncoding RNA,lncRNA)是从哺乳动物基因组中转录出来缺乏蛋白质编码潜力的核酸分子,主要从表观遗传学、转录调控和转录后调控3个方面实现基因表达调控,或者直接参与调节蛋白质活性。随着测序技术的进展,发现lncRNA可以充当微小RNA(microRNA,miRNA)的竞争性内源RNA,再进一步调节mRNA 的表达。目前研究证实 lncRNA⁃miRNA⁃mRNA轴与心血管疾病的发病机制密切相关,文章介绍该轴在心血管疾病发病中的最新进展。

    Abstract

    Long non ⁃coding RNA(lncRNA)is a kind of nucleic acid molecule which is transcribed from the mammalian genome and lacks protein⁃coding potential,it mainly realizes the regulation of gene expression from three aspects of epigenetics,transcriptional regulation and post ⁃ transcriptional regulation,or directly participates in regulating protein activity. With the development of sequencing technology,it has been found that lncRNA can be used as miRNA sponge to further regulate mRNA expression,and the lncRNA ⁃miRNA ⁃mRNA axis plays an important role in the pathogenesis of diseases. Current researches confirm that the lncRNA ⁃ miRNA ⁃ mRNA axis is closely related to the pathogenesis of cardiovascular diseases. In this review,we summarize the latest developments in the known roles of this axis in the pathogenesis of cardiovascular diseases.

    关键词

    心血管疾病lncRNAmiRNAmRNA

    Keywords

    cardiovascular diseaselncRNAmiRNAmRNA

  • 由于不健康的生活方式和人口老龄化的进一步加重,心血管疾病(cardiovascular disease,CVD)的发病率逐年提升[1],治疗CVD已成为现代医学领域的热点问题。虽然随着新型药物的临床应用和医学科技水平的不断提高,CVD的治疗已经取得很大进展,但仍是最常见的死因,给患者带来了沉重的健康和经济压力[2]。因此有必要寻求其潜在的分子机制以探索更有效的预防和治疗措施。

  • 全转录组分析发现RNA聚合酶Ⅱ(RNA⁃pol Ⅱ) 转录而来的非编码RNA(non⁃coding RNA,ncRNA)比蛋白质编码的mRNA更多,并且与疾病相关的单核苷酸多态性和突变在ncRNA基因座附近显著富集[3]。另有研究发现ncRNA广泛参与基因调控网络[4],表明可以从ncRNA角度研究疾病的发生、进展等。

  • 1 非编码RNA治疗心血管疾病的作用机制

  • 非编码RNA是指不编码蛋白质的RNA。它们主要分为小分子ncRNA和较长的ncRNA,前一组包括microRNA、小干扰RNA、核内小分子RNA、piwi相互作用RNA和转运RNA等,后一组包括核糖体RNA、天然反义转录本和长链非编码RNA[5]

  • 长链非编码RNA(long non⁃coding RNA,lncRNA) 是最广泛的ncRNA亚群,涉及多种CVD危险因素,包括病理性肥大、血管疾病、血脂异常和代谢综合征等[6]。 lncRNA是长度大于200个核苷酸的ncRNA,其作用机制与亚细胞定位有关。定位于细胞质的lncRNA主要影响mRNA的稳定性[7],调节翻译潜能[8],或者作为竞争性内源RNA(competing endogenous RNA,ceRNA)[9] 等发挥作用。而定位于细胞核的lncRNA则主要通过调节染色质发挥作用,包括染色质的结构[10]、重塑[11] 等,或与DNA相互作用形成RNA⁃DNA复合物以重编程基因表达[12],充当分子支架,激活或抑制转录[13]

  • 微小RNA(microRNA,miRNA)是最具代表性的小分子非编码RNA类,主要引发基因表达的转录后调节。miRNA长约22个核苷酸,其主要作用是通过结合和沉默特定的目标mRNA来抑制蛋白质的表达,从而降低蛋白质的合成[14]。鉴于miRNA与多种心血管疾病相关,如心肌肥厚、心律失常、高血压等[15],因此可以将miRNA和lncRNA结合起来讨论其在CVD中的作用机制。

  • 此外,目前多种研究表明lncRNA可以与miRNA相互作用。lncRNA在转录过程中类似于mRNA,并具有结构相似性。因此,除靶向mRNA以外,RNA诱导的沉默复合物中的miRNA还可靶向调节lncRNA,并通过不完美的碱基配对降低其结构和功能稳定性[16]。有趣的是,miRNA也可以通过某些机制增强lncRNA表达。研究表明成熟的细胞质miR⁃ NA可以进入细胞核并调节mRNA和ncRNA的核转录[17]。而“microRNA sponges”机制[18] 以及随后提出的伪靶假说、稀释效应和天然miRNA海绵等理论被总结成的ceRNA假说[9] 表明,带有miRNA反应元件的天然ceRNA在细胞内可以通过与靶miRNA结合而竞争阻断其功能。作为细胞内最重要的ceR⁃ NA之一,lncRNA可能参与lncRNA⁃miRNA⁃mRNA途径[19]。在ceRNA网络中,lncRNA可以通过自身的miRNA反应元件吸附目标miRNA,并抑制由miRNA介导的靶向mRNA降解,这也是lncRNA参与的常见转录后调控机制之一[20]

  • 2 各种心血管疾病中的lncRNA⁃miRNA⁃mRNA轴

  • 2.1 动脉粥样硬化(atherosclerosis,AS)

  • 动脉粥样硬化是世界范围内CVD死亡的主要原因[21],其发展是一个复杂的病理化过程,最初由内皮细胞激活促进,随后炎症细胞募集、平滑肌细胞增殖[22-23]。新出现的证据表明,lncRNA、miRNA在血管疾病中发挥重要作用[24-25]。动脉内膜中的氧化低密度脂蛋白(oxidation low lipoprotein,ox⁃LDL)通过介导内皮功能障碍或激活内皮细胞,促进AS的发展[26]。人冠状动脉内皮细胞在ox⁃LDL刺激后, Malat1表达升高,并可通过影响miR⁃155抑制炎性细胞因子的释放,从而增加细胞信号转导抑制因子1 (SOSC1)水平,抑制JAK⁃STAT通路,抑制AS[27]。血管平滑肌细胞是AS发展的关键因素[28]。人主动脉平滑肌细胞(HASMC)经ox⁃LDL刺激后,TNK2⁃AS1表达上调,并可以作为miR⁃150⁃5p的ceRNA调节血管内皮生长因子A(VEGFA)和成纤维细胞生长因子1(FGF1)的表达促进细胞的增殖和迁移,促进AS斑块的形成[29]。HASMC在经血小板衍生生长因子刺激后,SNHG16表达上调,通过生物信息学分析和荧光素酶报告基因测定证实SNHG16通过作为miR ⁃ 205的ceRNA调节Smad2表达也可促进HASMC增殖和迁移[30]。巨噬细胞衍生而来的泡沫细胞可形成最早的粥样硬化病变中的脂质条纹,在ox⁃LDL刺激人巨噬细胞后,UCA1靶向miR⁃206加重氧化应激和凋亡,促进AS[31]。平行于血管腔表面的层流切应力在调节抗炎、抗粘连和抗AS中起关键作用,从而影响AS的发展。人脐静脉内皮细胞经过层流切应力处理后,AF131217.1表达升高,随后靶向miR⁃128⁃3p/KLF4轴通过抑制内皮细胞炎症,在AS的发病机制中起抗AS的作用[32]。由此可知, lncRNA⁃miRNA⁃mRNA轴与AS息息相关(表1)。

  • 2.2 心肌梗死(myocardial infarction,MI)

  • 由急性冠状动脉闭塞引起的急性心肌梗死是CVD患者死亡的主要原因之一,每年疾病影响范围超过700万人[33]。ceRNA是lncRNA调节CVD进展的新形式,该功能已被广泛报道用于调节心脏重塑、血管平滑肌和内皮细胞的行为[34]。MI的主要原因是血液供应的长期中断,导致心脏某些部位缺乏营养和氧气,最终导致死亡[33]。研究发现缺氧损伤的H9c2细胞中ANRIL表达显著增强,沉默ANRIL可加重缺氧诱导的损伤,并通过调节miR⁃7⁃5p增加SIRT1表达,在缺氧损伤的H9c2细胞中发挥心脏保护作用,为治疗MI提供新思路[35]。缺血⁃再灌注损伤(I/R) 是MI患者心脏保护的关键治疗靶点[36]。I/R发病机制主要集中在氧自由基、钙超载、炎症反应、线粒体损伤、细胞死亡、内皮细胞损伤和自噬[37-38]。而自噬是衰老、炎症、肿瘤代谢和心血管疾病的重要过程[39],在心肌细胞中,自噬维持线粒体的更新,有助于满足心脏的能量需求[40]。研究发现,2810403D21Rik/Mirf是一种新型抗自噬性lncRNA,沉默该lncRNA可导致miR26a上调,随后通过靶向Usp15促进心肌细胞的自噬和减轻心脏损伤,改善心脏功能[41]。然而,自噬在MI中的作用仍然具有争议。根据压力的情况,自噬在MI中可以是保护性的或适应不良的。自噬功能障碍可能导致MI后心肌I/R和心室重构,甚至可能引发细胞凋亡和坏死[42]。如APF是一种自噬促进因子,当APF表达下降时,可通过作为miR⁃188⁃3p的ceRNA调节ATG7从而抑制自噬和MI[43]。同样,AK139128也是一种自噬促进因子,其表达显著上调时,通过负调节miR⁃499/FOXO4轴促进自噬和心肌细胞凋亡[44]。心肌细胞凋亡是扩大梗死范围的另一个重要因素,梗死早期和晚期均存在凋亡现象。GAS5在MI后表达上调,沉默GAS5可通过靶向miR⁃525⁃5p/CALM2轴抑制心肌细胞凋亡,并改善梗死后心肌细胞的活力[45]。综上,可以发现lncRNA⁃miRNA⁃mRNA轴为MI的治疗提供了新的治疗靶点(表1)。

  • 表1 心血管疾病中的lncRNA⁃miRNA⁃mRNA轴

  • Table1 lncRNA⁃miRNA⁃mRNA axes in cardiovascular diseases

  • 2.3 心脏肥大(cardiac hypertrophy,CH)

  • 心脏肥大是心脏对压力/容量超负荷的适应性反应,以在早期维持心脏功能。然而,持续性的CH通常会引发适应不良的心脏重塑,从而导致依从性降低、心力衰竭和猝死的风险增加。因此必须寻找有效的治疗手段,以抑制适应不良的肥大和随之而来的心力衰竭。研究常用主动脉缩窄术(transverse aortic constriction,TAC)建立的小鼠心脏肥厚模型和血管紧张素Ⅱ或去氧肾上腺素诱导的细胞肥大模型进行实验。在肥厚模型中首次验证的lncRNA为CHRF,其可以靶向miR⁃489,并进一步调节Myd88的表达水平,从而激活肥大反应[15]。接下来在TAC动物模型和诱导的细胞肥大模型中验证了多种lncRNA可以通过ceRNA机制调节靶基因从而影响CH。如HOTAIR通过miR⁃19/PTEN轴在CH中发挥负调节因子的功能[46],MAGI1⁃IT1通过靶向miR⁃302e/DKK1轴使Wnt/β⁃连环蛋白途径失活而在CH中起负调节剂的作用[47]。MIAT通过在心肌细胞中作为miR⁃93的海绵而正调节TLR4的表达,在CH中起正向调节作用[48]。用主动脉缩窄法诱导肾血管高血压建立的肥厚模型中,发现CYTOR可能通过miR⁃155和下游IKKi和NF⁃κB信号转导在CH中起保护作用,最可能通过作为miR⁃155的ceRNA来抵消miR⁃155介导的IKBKE抑制[49]。由此表明,该轴也可参与CH的发生机制,从而作为肥大的治疗靶点。

  • 2.4 糖尿病性心肌病(diabetic cardiomyopathy,DCM)

  • 随着lncRNA⁃miRNA⁃mRNA轴在心肌病中的研究进展,人们对DCM的分子机制有了进一步的认识。DCM是心脏病的一种特殊形式,它是由对心脏组织中胰岛素代谢作用的抵抗、代偿性高胰岛素血症和高血糖引起的,而这种疾病的发生独立于其他心脏危险因素[50],并且越来越多的研究表明氧化应激、炎症、线粒体功能障碍、肾素 ⁃ 血管紧张素系统激活、心肌细胞凋亡都参与了DCM的发病机制[51]。通过在腹膜内注射链脲佐菌素诱导DCM小鼠模型,并在该模型中发现了几条lncRNA⁃miRNA⁃mRNA轴。DCRF可以作为miR ⁃551b ⁃5p的ceRNA增加PCDH17的表达,从而增加心肌细胞自噬,促进DCM的进展[52]。MIAT可以通过作为miR⁃22⁃3p的ceRNA上调DAPK2表达,从而导致心肌细胞凋亡,参与DCM的进展[53]。MEG3已被证明可参与多种心血管疾病的发展[54],在DCM中,MEG3在高糖处理的AC16细胞中可作为抑制miR⁃145表达的ceRNA,减少miR⁃145对PDCD4的抑制作用,从而减轻AC16细胞凋亡[55(] 表1)。

  • 2.5 心房颤动(atrial fibrillation,AF)

  • 心房颤动是目前临床上难以攻克的心律失常,会增加心力衰竭和缺血性卒中的风险,也是造成人群发病率和死亡率高的原因之一[56]。已知CAC⁃ NA1C是房颤发展过程中的关键生物标志物[57], YY1诱导的KCNQ1OT1上调可通过调节miR⁃384/CACNA1C轴增加血管紧张素Ⅱ诱导的心房颤动[58]。电重构在AF的发生和维持中起关键作用,TCONS 00075467可通过作为miR⁃328的ceRNA改变CAC⁃ NA1C的表达从而调节心房电重构影响房颤[59]。心房纤维化是AF中心房结构重构的标志,已成为房颤的重要病理生理因素[60]。PVT1可以充当miR⁃128⁃3p的海绵并消除miR⁃128⁃3p对Sp1的抑制作用,进而激活TGF⁃β1/Smad通路,促进成纤维细胞增殖,胶原产生和小鼠心房纤维化[61],而研究表明,TGF⁃β1通过Smad蛋白产生促纤维化作用,可以增强心房纤维化和AF[62(] 表1)。由此可知,lncRNA⁃miRNA⁃mRNA轴可参与AF的发病机制,有助于找到AF的新治疗靶点。

  • 2.6 钙化性主动脉瓣疾病(calcified aortic valve dis⁃ ease,CAVD)

  • CAVD在成人中具有较高的发病率和死亡率,并且目前没有有效的医学手段来预防或减缓疾病过程[63]。其瓣叶钙化的主要原因是主动脉瓣叶中静息的瓣膜间质细胞(valve interstitial cell,VIC)被激活并经历表型转变成为成骨细胞样细胞[64],因此可以通过抑制成骨细胞分化以防止VIC的转化,从而阻止甚至逆转CAVD的进展。研究发现,TUG1可以通过海绵状miR⁃204⁃5p调节Runx2的表达[65], MALAT1可以通过靶向miR⁃204调节Smad4的表达[66],AFAP1 ⁃ AS1也可以通过调节miR ⁃ 155/SMAD5轴[67] 促进VIC的成骨分化,从而促进CAVD的形成(表1),表明lncRNA在CAVD中可作为新治疗靶点的潜力。

  • 3 lncRNA⁃miRNA⁃mRNA轴在心血管疾病的病理生理学中的作用

  • 应激、细胞凋亡、自噬、坏死、纤维化以及心肌细胞、内皮细胞、心脏成纤维细胞和血管平滑肌细胞的增殖和迁移都有助于CVD的发生发展,而上述研究证明该轴在这些CVD的进展机制中起重要作用。如TNK2⁃AS1可通过靶向miR ⁃ 150⁃5p调节VEGFA和FGF1的表达从而调节血管平滑肌细胞的增殖和迁移[29],GAS5可通过靶向miR ⁃525⁃5p/CALM2轴调节心肌细胞的凋亡和增殖能力[45], PVT1可以作为miR⁃128⁃3p的ceRNA消除其对Sp1的抑制作用,进而激活TGF⁃β1/Smad通路,促进成纤维细胞增殖和小鼠心房纤维化[61]

  • 4 结论和展望

  • 近年来,随着ncRNA在多种疾病发展过程中表现出独特的功能,对于lncRNA在心血管疾病发病机制中的认识也进一步加深。本文总结了一些lncRNA ⁃miRNA ⁃mRNA轴在CVD中的作用机制。 lncRNA可以通过ceRNA机制正向或负向调节疾病的进展,以作为疾病的新型治疗靶点。并且同一种lncRNA可以靶向不同的miRNA,同一种miRNA也可以被不同的lncRNA靶控,再通过不同的信号途径发挥效应。但目前大部分实验只局限于动物和细胞,尚未运用到临床,需要进行大规模的临床研究,以观察lncRNA⁃miRNA⁃mRNA轴的调节能否做为药物治疗的靶点或作为疾病进展的标志物,最终将ncRNA运用于临床实践。

  • 参考文献

    • [1] TRIPOSKIADIS F,XANTHOPOULOS A,BUTLER J.Cardiovascular aging and heart failure:JACC review top⁃ ic of the week[J].J Am Coll Cardiol,2019,74(6):804-813

    • [2] BENJAMIN E J,BLAHA M J,CHIUVE S E,et al.Heart disease and stroke statistics ⁃ 2017 update:a report from the American Heart Association[J].Circulation,2017,135(10):e146-e603

    • [3] KAIKKONEN M U,ADELMAN K.Emerging roles of non⁃ coding RNA transcription[J].Trends Biochem Sci,2018,43(9):654-667

    • [4] ANASTASIADOU E,JACOB L S,SLACK F J.Non ⁃cod⁃ ing RNA networks in cancer[J].Nat Rev Cancer,2018,18(1):5-18

    • [5] LIU S,YANG Y,JIANG S,et al.Understanding the role of non⁃coding RNA(ncRNA)in stent restenosis[J].Ath⁃ erosclerosis,2018,272:153-161

    • [6] SALLAM T,SANDHU J,TONTONOZ P.Long noncoding RNA discovery in cardiovascular disease:decoding form to function[J].Circ Res,2018,122(1):155-166

    • [7] ZHANG Y,DU W,YANG B.Long non ⁃coding RNAs as new regulators of cardiac electrophysiology and arrhyth⁃ mias:molecular mechanisms,therapeutic implications and challenges[J].Pharmacol Ther,2019,203:107389

    • [8] CARRIERI C,CIMATTI L,BIAGIOLI M,et al.Long non⁃ coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat[J].Nature,2012,491(7424):454-457

    • [9] SALMENA L,POLISENO L,TAY Y,et al.A CeRNA hy⁃ pothesis:the Rosetta stone of a hidden RNA language?[J].Cell,2011,146(3):353-358

    • [10] DYKES I M,EMANUELI C.Transcriptional and post ⁃ transcriptional gene regulation by long non ⁃ coding RNA [J].Genomics Proteomics Bioinformatics,2017,15(3):177-186

    • [11] JÉGU T,AEBY E,LEE J T.The X chromosome in space [J].Nat Rev Genet,2017,18(6):377-389

    • [12] WANG F,CHAINANI P,WHITE T,et al.Deep learning identifies genome⁃wide DNA binding sites of long noncod⁃ ing RNAs[J].RNA Biol,2018,15(12):1468-1476

    • [13] ENGREITZ J M,HAINES J E,PEREZ E M,et al.Local regulation of gene expression by lncRNA promoters,tran⁃ scription and splicing[J].Nature,2016,539(7629):452-455

    • [14] BARWARI T,JOSHI A,MAYR M.MicroRNAs in cardio⁃ vascular disease[J].J Am Coll Cardiol,2016,68(23):2577-2584

    • [15] 孟荔,史爱武.微小RNA在心血管疾病中的研究进展[J].南京医科大学学报(自然科学版),2018,38(4):562-568

    • [16] BALLANTYNE M D,MCDONALD R A,BAKER A H.ln⁃ cRNA/MicroRNA interactions in the vasculature[J].Clin Pharmacol Ther,2016,99(5):494-501

    • [17] LIANG H,ZHANG J,ZEN K,et al.Nuclear microRNAs and their unconventional role in regulating non ⁃ coding RNAs[J].Protein Cell,2013,4(5):325-330

    • [18] EBERT M S,NEILSON J R,SHARP P A.MicroRNA sponges:competitive inhibitors of small RNAs in mamma⁃ lian cells[J].Nat Methods,2007,4(9):721-726

    • [19] QU J,LI M,ZHONG W,et al.Competing endogenous RNA in cancer:a new pattern of gene expression regula⁃ tion[J].Int J Clin Exp Med,2015,8(10):17110-17116

    • [20] WANG F,YANG H,DENG Z,et al.HOX antisense lin⁃ cRNA HOXA⁃AS2 promotes tumorigenesis of hepatocellu⁃ lar carcinoma[J].Cell Physiol Biochem,2016,40(1/2):287-296

    • [21] XU S,KAMATO D,LITTLE P J,et al.Targeting epi⁃ genetics and non ⁃ coding RNAs in atherosclerosis:from mechanisms to therapeutics[J].Pharmacol Ther,2019,196:15-43

    • [22] GIMBRONE M A,GARCÍA ⁃ CARDEÑA G.Endothelial cell dysfunction and the pathobiology of atherosclerosis [J].Circ Res,2016,118(4):620-636

    • [23] BASATEMUR G L,JØRGENSEN H F,CLARKE M C H,et al.Vascular smooth muscle cells in atherosclerosis[J].Nat Rev Cardiol,2019,16(12):727-744

    • [24] BOON R A,JAÉ N,HOLDT L,et al.Long noncoding RNAs:from clinical genetics to therapeutic targets?[J].J Am Coll Cardiol,2016,67(10):1214-1226

    • [25] THUM T,CONDORELLI G.Long noncoding RNAs and microRNAs in cardiovascular pathophysiology[J].Circ Res,2015,116(4):751-762

    • [26] STEINBERG D,WITZTUM J L.Oxidized low ⁃density li⁃ poprotein and atherosclerosis[J].Arterioscler Thromb Vasc Biol,2010,30(12):2311-2316

    • [27] LI S,SUN Y,ZHONG L,et al.The suppression of ox⁃LDL⁃ induced inflammatory cytokine release and apoptosis of HCAECs by long non⁃coding RNA⁃MALAT1 via regulat⁃ ing microRNA ⁃155/SOCS1 pathway[J].Nutr Metab Car⁃ diovasc Dis,2018,28(11):1175-1187

    • [28] LI M N,QIAN M,KYLER K,et al.Endothelial⁃vascular smooth muscle cells interactions in atherosclerosis[J].Front Cardiovasc Med,2018,5:151

    • [29] CAI T,CUI X,ZHANG K,et al.LncRNA TNK2⁃AS1 regu⁃ lated ox⁃LDL⁃stimulated HASMC proliferation and migra⁃ tion via modulating VEGFA and FGF1 expression by sponging miR⁃150⁃5p[J].J Cell Mol Med,2019,23(11):7289-7298

    • [30] LIN Y,TIAN G,ZHANG H,et al.Long non⁃coding RNA SNHG16 regulates human aortic smooth muscle cell pro⁃ liferation and migration via sponging miR⁃205 and modu⁃ lating Smad2[J].J Cell Mol Med,2019,23(10):6919-6929

    • [31] HU X,MA R,FU W,et al.LncRNA UCA1 sponges miR⁃ 206 to exacerbate oxidative stress and apoptosis induced by ox ⁃ LDL in human macrophages[J].J Cell Physiol,2019,234(8):14154-14160

    • [32] LU Q,MENG Q,QI M,et al.Shear ⁃ sensitive lncRNA AF1312171 inhibits inflammation in HUVECs via regula⁃ tion of KLF4[J].Hypertension,2019,73(5):e25-e34

    • [33] ANDERSON J L,MORROW D A.Acute myocardial in⁃ farction[J].N Engl J Med,2017,376(21):2053-2064

    • [34] SONG X,SHAN D,CHEN J,et al.miRNAs and lncRNAs in vascular injury and remodeling[J].Sci China Life Sci,2014,57(8):826-835

    • [35] SHU L,ZHANG W,HUANG C,et al.lncRNA ANRIL protects H9c2 cells against hypoxia ⁃ induced injury through targeting the miR ⁃ 7 ⁃ 5p/SIRT1 axis[J].J Cell Physiol,2020,235(2):1175-1183

    • [36] LUO H,WANG J,LIU D,et al.The lncRNA H19/miR ⁃ 675 axis regulates myocardial ischemic and reperfusion injury by targeting PPARα[J].Mol Immunol,2019,105:46-54

    • [37] HAUSENLOY D J,YELLON D M.Myocardial ischemia⁃ reperfusion injury:a neglected therapeutic target[J].J Clin Invest,2013,123(1):92-100

    • [38] XUAN F,JIAN J,LIN X,et al.17⁃methoxyl⁃7⁃hydroxy⁃ benzene ⁃furanchalcone ameliorates myocardial ischemia/reperfusion injury in rat by inhibiting apoptosis and au⁃ tophagy via the PI3K ⁃Akt signal pathway[J].Cardiovasc Toxicol,2017,17(1):79-87

    • [39] GIAMPIERI F,AFRIN S,FORBES ⁃HERNANDEZ T Y,et al.Autophagy in human health and disease:novel ther⁃ apeutic opportunities[J].Antioxid Redox Signal,2019,30(4):577-634

    • [40] TANEIKE M,YAMAGUCHI O,NAKAI A,et al.Inhibi⁃ tion of autophagy in the heart induces age⁃related cardio⁃ myopathy[J].Autophagy,2010,6(5):600-606

    • [41] LIANG H,SU X,WU Q,et al.LncRNA 2810403D21Rik/Mirf promotes ischemic myocardial injury by regulating autophagy through targeting Mir26a[J].Autophagy,2020,16(6):1077-1091

    • [42] TANAKA Y,GUHDE G,SUTER A,et al.Accumulation of autophagic vacuoles and cardiomyopathy in LAMP ⁃ 2⁃ deficient mice[J].Nature,2000,406(6798):902-906

    • [43] WANG K,LIU C Y,ZHOU L Y,et al.APF lncRNA regu⁃ lates autophagy and myocardial infarction by targeting miR⁃188⁃3p[J].Nat Commun,2015,6:6779

    • [44] ZHU Z,ZHAO C.WITHDRAWN:LncRNA AK139128 promotes cardiomyocyte autophagy and apoptosis in myo⁃ cardial hypoxia ⁃ reoxygenation injury[J].Life Sci,2019:116705

    • [45] ZHANG Y,HOU Y M,GAO F,et al.lncRNA GAS5 regu⁃ lates myocardial infarction by targeting the miR ⁃525⁃5p/CALM2 axis[J].J Cell Biochem,2019,120(11):18678-18688

    • [46] LAI Y,HE S,MA L,et al.HOTAIR functions as a com⁃ peting endogenous RNA to regulate PTEN expression by inhibiting miR ⁃ 19 in cardiac hypertrophy[J].Mol Cell Biochem,2017,432(1/2):179-187

    • [47] ZHANG Q,WANG F,WANG F,et al.Long noncoding RNA MAGI1⁃IT1 regulates cardiac hypertrophy by modu⁃ lating miR ⁃ 302e/DKK1/Wnt/beta ⁃ catenin signaling path⁃ way[J].J Cell Physiol,2020,235(1):245-253

    • [48] LI Y,WANG J,SUN L,et al.LncRNA myocardial infarc⁃ tion ⁃ associated transcript(MIAT)contributed to cardiac hypertrophy by regulating TLR4 via miR ⁃ 93[J].Eur J Pharmacol,2018,818:508-517

    • [49] YUAN Y,WANG J,CHEN Q,et al.Long non ⁃ coding RNA cytoskeleton regulator RNA(CYTOR)modulates pathological cardiac hypertrophy through miR⁃155⁃medi⁃ ated IKKi signaling[J].Biochim Biophys Acta Mol Basis Dis,2019,1865(6):1421-1427

    • [50] JIA G,WHALEY ⁃CONNELL A,SOWERS J R.Diabetic cardiomyopathy:a hyperglycaemia⁃ and insulin⁃resistance⁃ induced heart disease[J].Diabetologia,2018,61(1):21-28

    • [51] BUGGER H,ABEL E D.Molecular mechanisms of diabet⁃ ic cardiomyopathy[J].Diabetologia,2014,57(4):660-671

    • [52] FENG Y,XU W,ZHANG W,et al.LncRNA DCRF regu⁃ lates cardiomyocyte autophagy by targeting miR⁃551b⁃5p in diabetic cardiomyopathy[J].Theranostics,2019,9(15):4558-4566

    • [53] ZHOU X,ZHANG W,JIN M,et al.lncRNA MIAT func⁃ tions as a competing endogenous RNA to upregulate DAPK2 by sponging miR⁃22⁃3p in diabetic cardiomyopa⁃ thy[J].Cell Death Dis,2017,8(7):e2929

    • [54] PICCOLI M T,GUPTA S K,VIERECK J,et al.Inhibition of the cardiac fibroblast⁃enriched lncRNA Meg3 prevents cardiac fibrosis and diastolic dysfunction[J].Circ Res,2017,121(5):575-583

    • [55] CHEN Y,ZHANG Z,ZHU D,et al.Long non⁃coding RNA MEG3 serves as a ceRNA for microRNA ⁃ 145 to induce apoptosis of AC16 cardiomyocytes under high glucose condition[J].Biosci Rep,2019,39(6):BSR20190444

    • [56] ZIMETBAUM P.Atrial fibrillation[J].Ann Intern Med,2017,166(5):ITC33-ITC48

    • [57] LI Z,WANG X,WANG W,et al.Altered long non⁃coding RNA expression profile in rabbit atria with atrial fibrilla⁃ tion:TCONS00075467 modulates atrial electrical remodeling by sponging miR ⁃ 328 to regulate CACNA1C[J].J Mol Cell Cardiol,2017,108:73-85

    • [58] LI X,DAI Y,YAN S,et al.Down ⁃ regulation of lncRNA KCNQ1OT1 protects against myocardial ischemia/reperfu⁃ sion injury following acute myocardial infarction[J].Bio⁃ chem Biophys Res Commun,2017,491(4):1026-1033

    • [59] LI M,WANG Y F,YANG X C,et al.Circulating long non⁃ coding RNA LIPCAR acts as a novel biomarker in pa⁃ tients with ST ⁃ segment elevation myocardial infarction [J].Med Sci Monit,2018,24:5064-5070

    • [60] SHEN C,KONG B,LIU Y,et al.YY1 ⁃induced upregula⁃ tion of lncRNA KCNQ1OT1 regulates angiotensin Ⅱ⁃in⁃ duced atrial fibrillation by modulating miR ⁃ 384b/CAC⁃ NA1C axis[J].Biochem Biophys Res Commun,2018,505(1):134-140

    • [61] CAO F,LI Z,DING W M,et al.LncRNA PVT1 regulates atrial fibrosis via miR⁃128⁃3p⁃SP1⁃TGF⁃β1⁃Smad axis in atrial fibrillation[J].Mol Med,2019,25(1):7

    • [62] GUO J,JIA F,JIANG Y,et al.Potential role of MG53 in the regulation of transforming ⁃growth ⁃factor ⁃β1⁃induced atrial fibrosis and vulnerability to atrial fibrillation[J].Exp Cell Res,2018,362(2):436-443

    • [63] BONOW R O,LEON M B,DOSHI D,et al.Management strategies and future challenges for aortic valve disease [J].Lancet,2016,387(10025):1312-1323

    • [64] YUTZEY K E,DEMER L L,BODY S C,et al.Calcific aortic valve disease:a consensus summary from the alli⁃ ance of investigators on calcific aortic valve disease[J].Arterioscler Thromb Vasc Biol,2014,34(11):2387-2393

    • [65] YU C,LI L,XIE F,et al.LncRNA TUG1 sponges miR ⁃ 204 ⁃ 5p to promote osteoblast differentiation through up⁃ regulating Runx2 in aortic valve calcification[J].Cardio⁃ vasc Res,2018,114(1):168-179

    • [66] XIAO X,ZHOU T,GUO S,et al.LncRNA MALAT1 sponges miR ⁃204 to promote osteoblast differentiation of human aortic valve interstitial cells through up⁃regulating Smad4[J].Int J Cardiol,2017,243:404-412

    • [67] HE W,LI F,ZHANG S,et al.LncRNA AFAP1⁃AS1 pro⁃ motes osteoblast differentiation of human aortic valve in⁃ terstitial cells through regulating miR ⁃ 155/SMAD5 axis [J].Mol Cell Probes,2020,50:101509

  • 参考文献

    • [1] TRIPOSKIADIS F,XANTHOPOULOS A,BUTLER J.Cardiovascular aging and heart failure:JACC review top⁃ ic of the week[J].J Am Coll Cardiol,2019,74(6):804-813

    • [2] BENJAMIN E J,BLAHA M J,CHIUVE S E,et al.Heart disease and stroke statistics ⁃ 2017 update:a report from the American Heart Association[J].Circulation,2017,135(10):e146-e603

    • [3] KAIKKONEN M U,ADELMAN K.Emerging roles of non⁃ coding RNA transcription[J].Trends Biochem Sci,2018,43(9):654-667

    • [4] ANASTASIADOU E,JACOB L S,SLACK F J.Non ⁃cod⁃ ing RNA networks in cancer[J].Nat Rev Cancer,2018,18(1):5-18

    • [5] LIU S,YANG Y,JIANG S,et al.Understanding the role of non⁃coding RNA(ncRNA)in stent restenosis[J].Ath⁃ erosclerosis,2018,272:153-161

    • [6] SALLAM T,SANDHU J,TONTONOZ P.Long noncoding RNA discovery in cardiovascular disease:decoding form to function[J].Circ Res,2018,122(1):155-166

    • [7] ZHANG Y,DU W,YANG B.Long non ⁃coding RNAs as new regulators of cardiac electrophysiology and arrhyth⁃ mias:molecular mechanisms,therapeutic implications and challenges[J].Pharmacol Ther,2019,203:107389

    • [8] CARRIERI C,CIMATTI L,BIAGIOLI M,et al.Long non⁃ coding antisense RNA controls Uchl1 translation through an embedded SINEB2 repeat[J].Nature,2012,491(7424):454-457

    • [9] SALMENA L,POLISENO L,TAY Y,et al.A CeRNA hy⁃ pothesis:the Rosetta stone of a hidden RNA language?[J].Cell,2011,146(3):353-358

    • [10] DYKES I M,EMANUELI C.Transcriptional and post ⁃ transcriptional gene regulation by long non ⁃ coding RNA [J].Genomics Proteomics Bioinformatics,2017,15(3):177-186

    • [11] JÉGU T,AEBY E,LEE J T.The X chromosome in space [J].Nat Rev Genet,2017,18(6):377-389

    • [12] WANG F,CHAINANI P,WHITE T,et al.Deep learning identifies genome⁃wide DNA binding sites of long noncod⁃ ing RNAs[J].RNA Biol,2018,15(12):1468-1476

    • [13] ENGREITZ J M,HAINES J E,PEREZ E M,et al.Local regulation of gene expression by lncRNA promoters,tran⁃ scription and splicing[J].Nature,2016,539(7629):452-455

    • [14] BARWARI T,JOSHI A,MAYR M.MicroRNAs in cardio⁃ vascular disease[J].J Am Coll Cardiol,2016,68(23):2577-2584

    • [15] 孟荔,史爱武.微小RNA在心血管疾病中的研究进展[J].南京医科大学学报(自然科学版),2018,38(4):562-568

    • [16] BALLANTYNE M D,MCDONALD R A,BAKER A H.ln⁃ cRNA/MicroRNA interactions in the vasculature[J].Clin Pharmacol Ther,2016,99(5):494-501

    • [17] LIANG H,ZHANG J,ZEN K,et al.Nuclear microRNAs and their unconventional role in regulating non ⁃ coding RNAs[J].Protein Cell,2013,4(5):325-330

    • [18] EBERT M S,NEILSON J R,SHARP P A.MicroRNA sponges:competitive inhibitors of small RNAs in mamma⁃ lian cells[J].Nat Methods,2007,4(9):721-726

    • [19] QU J,LI M,ZHONG W,et al.Competing endogenous RNA in cancer:a new pattern of gene expression regula⁃ tion[J].Int J Clin Exp Med,2015,8(10):17110-17116

    • [20] WANG F,YANG H,DENG Z,et al.HOX antisense lin⁃ cRNA HOXA⁃AS2 promotes tumorigenesis of hepatocellu⁃ lar carcinoma[J].Cell Physiol Biochem,2016,40(1/2):287-296

    • [21] XU S,KAMATO D,LITTLE P J,et al.Targeting epi⁃ genetics and non ⁃ coding RNAs in atherosclerosis:from mechanisms to therapeutics[J].Pharmacol Ther,2019,196:15-43

    • [22] GIMBRONE M A,GARCÍA ⁃ CARDEÑA G.Endothelial cell dysfunction and the pathobiology of atherosclerosis [J].Circ Res,2016,118(4):620-636

    • [23] BASATEMUR G L,JØRGENSEN H F,CLARKE M C H,et al.Vascular smooth muscle cells in atherosclerosis[J].Nat Rev Cardiol,2019,16(12):727-744

    • [24] BOON R A,JAÉ N,HOLDT L,et al.Long noncoding RNAs:from clinical genetics to therapeutic targets?[J].J Am Coll Cardiol,2016,67(10):1214-1226

    • [25] THUM T,CONDORELLI G.Long noncoding RNAs and microRNAs in cardiovascular pathophysiology[J].Circ Res,2015,116(4):751-762

    • [26] STEINBERG D,WITZTUM J L.Oxidized low ⁃density li⁃ poprotein and atherosclerosis[J].Arterioscler Thromb Vasc Biol,2010,30(12):2311-2316

    • [27] LI S,SUN Y,ZHONG L,et al.The suppression of ox⁃LDL⁃ induced inflammatory cytokine release and apoptosis of HCAECs by long non⁃coding RNA⁃MALAT1 via regulat⁃ ing microRNA ⁃155/SOCS1 pathway[J].Nutr Metab Car⁃ diovasc Dis,2018,28(11):1175-1187

    • [28] LI M N,QIAN M,KYLER K,et al.Endothelial⁃vascular smooth muscle cells interactions in atherosclerosis[J].Front Cardiovasc Med,2018,5:151

    • [29] CAI T,CUI X,ZHANG K,et al.LncRNA TNK2⁃AS1 regu⁃ lated ox⁃LDL⁃stimulated HASMC proliferation and migra⁃ tion via modulating VEGFA and FGF1 expression by sponging miR⁃150⁃5p[J].J Cell Mol Med,2019,23(11):7289-7298

    • [30] LIN Y,TIAN G,ZHANG H,et al.Long non⁃coding RNA SNHG16 regulates human aortic smooth muscle cell pro⁃ liferation and migration via sponging miR⁃205 and modu⁃ lating Smad2[J].J Cell Mol Med,2019,23(10):6919-6929

    • [31] HU X,MA R,FU W,et al.LncRNA UCA1 sponges miR⁃ 206 to exacerbate oxidative stress and apoptosis induced by ox ⁃ LDL in human macrophages[J].J Cell Physiol,2019,234(8):14154-14160

    • [32] LU Q,MENG Q,QI M,et al.Shear ⁃ sensitive lncRNA AF1312171 inhibits inflammation in HUVECs via regula⁃ tion of KLF4[J].Hypertension,2019,73(5):e25-e34

    • [33] ANDERSON J L,MORROW D A.Acute myocardial in⁃ farction[J].N Engl J Med,2017,376(21):2053-2064

    • [34] SONG X,SHAN D,CHEN J,et al.miRNAs and lncRNAs in vascular injury and remodeling[J].Sci China Life Sci,2014,57(8):826-835

    • [35] SHU L,ZHANG W,HUANG C,et al.lncRNA ANRIL protects H9c2 cells against hypoxia ⁃ induced injury through targeting the miR ⁃ 7 ⁃ 5p/SIRT1 axis[J].J Cell Physiol,2020,235(2):1175-1183

    • [36] LUO H,WANG J,LIU D,et al.The lncRNA H19/miR ⁃ 675 axis regulates myocardial ischemic and reperfusion injury by targeting PPARα[J].Mol Immunol,2019,105:46-54

    • [37] HAUSENLOY D J,YELLON D M.Myocardial ischemia⁃ reperfusion injury:a neglected therapeutic target[J].J Clin Invest,2013,123(1):92-100

    • [38] XUAN F,JIAN J,LIN X,et al.17⁃methoxyl⁃7⁃hydroxy⁃ benzene ⁃furanchalcone ameliorates myocardial ischemia/reperfusion injury in rat by inhibiting apoptosis and au⁃ tophagy via the PI3K ⁃Akt signal pathway[J].Cardiovasc Toxicol,2017,17(1):79-87

    • [39] GIAMPIERI F,AFRIN S,FORBES ⁃HERNANDEZ T Y,et al.Autophagy in human health and disease:novel ther⁃ apeutic opportunities[J].Antioxid Redox Signal,2019,30(4):577-634

    • [40] TANEIKE M,YAMAGUCHI O,NAKAI A,et al.Inhibi⁃ tion of autophagy in the heart induces age⁃related cardio⁃ myopathy[J].Autophagy,2010,6(5):600-606

    • [41] LIANG H,SU X,WU Q,et al.LncRNA 2810403D21Rik/Mirf promotes ischemic myocardial injury by regulating autophagy through targeting Mir26a[J].Autophagy,2020,16(6):1077-1091

    • [42] TANAKA Y,GUHDE G,SUTER A,et al.Accumulation of autophagic vacuoles and cardiomyopathy in LAMP ⁃ 2⁃ deficient mice[J].Nature,2000,406(6798):902-906

    • [43] WANG K,LIU C Y,ZHOU L Y,et al.APF lncRNA regu⁃ lates autophagy and myocardial infarction by targeting miR⁃188⁃3p[J].Nat Commun,2015,6:6779

    • [44] ZHU Z,ZHAO C.WITHDRAWN:LncRNA AK139128 promotes cardiomyocyte autophagy and apoptosis in myo⁃ cardial hypoxia ⁃ reoxygenation injury[J].Life Sci,2019:116705

    • [45] ZHANG Y,HOU Y M,GAO F,et al.lncRNA GAS5 regu⁃ lates myocardial infarction by targeting the miR ⁃525⁃5p/CALM2 axis[J].J Cell Biochem,2019,120(11):18678-18688

    • [46] LAI Y,HE S,MA L,et al.HOTAIR functions as a com⁃ peting endogenous RNA to regulate PTEN expression by inhibiting miR ⁃ 19 in cardiac hypertrophy[J].Mol Cell Biochem,2017,432(1/2):179-187

    • [47] ZHANG Q,WANG F,WANG F,et al.Long noncoding RNA MAGI1⁃IT1 regulates cardiac hypertrophy by modu⁃ lating miR ⁃ 302e/DKK1/Wnt/beta ⁃ catenin signaling path⁃ way[J].J Cell Physiol,2020,235(1):245-253

    • [48] LI Y,WANG J,SUN L,et al.LncRNA myocardial infarc⁃ tion ⁃ associated transcript(MIAT)contributed to cardiac hypertrophy by regulating TLR4 via miR ⁃ 93[J].Eur J Pharmacol,2018,818:508-517

    • [49] YUAN Y,WANG J,CHEN Q,et al.Long non ⁃ coding RNA cytoskeleton regulator RNA(CYTOR)modulates pathological cardiac hypertrophy through miR⁃155⁃medi⁃ ated IKKi signaling[J].Biochim Biophys Acta Mol Basis Dis,2019,1865(6):1421-1427

    • [50] JIA G,WHALEY ⁃CONNELL A,SOWERS J R.Diabetic cardiomyopathy:a hyperglycaemia⁃ and insulin⁃resistance⁃ induced heart disease[J].Diabetologia,2018,61(1):21-28

    • [51] BUGGER H,ABEL E D.Molecular mechanisms of diabet⁃ ic cardiomyopathy[J].Diabetologia,2014,57(4):660-671

    • [52] FENG Y,XU W,ZHANG W,et al.LncRNA DCRF regu⁃ lates cardiomyocyte autophagy by targeting miR⁃551b⁃5p in diabetic cardiomyopathy[J].Theranostics,2019,9(15):4558-4566

    • [53] ZHOU X,ZHANG W,JIN M,et al.lncRNA MIAT func⁃ tions as a competing endogenous RNA to upregulate DAPK2 by sponging miR⁃22⁃3p in diabetic cardiomyopa⁃ thy[J].Cell Death Dis,2017,8(7):e2929

    • [54] PICCOLI M T,GUPTA S K,VIERECK J,et al.Inhibition of the cardiac fibroblast⁃enriched lncRNA Meg3 prevents cardiac fibrosis and diastolic dysfunction[J].Circ Res,2017,121(5):575-583

    • [55] CHEN Y,ZHANG Z,ZHU D,et al.Long non⁃coding RNA MEG3 serves as a ceRNA for microRNA ⁃ 145 to induce apoptosis of AC16 cardiomyocytes under high glucose condition[J].Biosci Rep,2019,39(6):BSR20190444

    • [56] ZIMETBAUM P.Atrial fibrillation[J].Ann Intern Med,2017,166(5):ITC33-ITC48

    • [57] LI Z,WANG X,WANG W,et al.Altered long non⁃coding RNA expression profile in rabbit atria with atrial fibrilla⁃ tion:TCONS00075467 modulates atrial electrical remodeling by sponging miR ⁃ 328 to regulate CACNA1C[J].J Mol Cell Cardiol,2017,108:73-85

    • [58] LI X,DAI Y,YAN S,et al.Down ⁃ regulation of lncRNA KCNQ1OT1 protects against myocardial ischemia/reperfu⁃ sion injury following acute myocardial infarction[J].Bio⁃ chem Biophys Res Commun,2017,491(4):1026-1033

    • [59] LI M,WANG Y F,YANG X C,et al.Circulating long non⁃ coding RNA LIPCAR acts as a novel biomarker in pa⁃ tients with ST ⁃ segment elevation myocardial infarction [J].Med Sci Monit,2018,24:5064-5070

    • [60] SHEN C,KONG B,LIU Y,et al.YY1 ⁃induced upregula⁃ tion of lncRNA KCNQ1OT1 regulates angiotensin Ⅱ⁃in⁃ duced atrial fibrillation by modulating miR ⁃ 384b/CAC⁃ NA1C axis[J].Biochem Biophys Res Commun,2018,505(1):134-140

    • [61] CAO F,LI Z,DING W M,et al.LncRNA PVT1 regulates atrial fibrosis via miR⁃128⁃3p⁃SP1⁃TGF⁃β1⁃Smad axis in atrial fibrillation[J].Mol Med,2019,25(1):7

    • [62] GUO J,JIA F,JIANG Y,et al.Potential role of MG53 in the regulation of transforming ⁃growth ⁃factor ⁃β1⁃induced atrial fibrosis and vulnerability to atrial fibrillation[J].Exp Cell Res,2018,362(2):436-443

    • [63] BONOW R O,LEON M B,DOSHI D,et al.Management strategies and future challenges for aortic valve disease [J].Lancet,2016,387(10025):1312-1323

    • [64] YUTZEY K E,DEMER L L,BODY S C,et al.Calcific aortic valve disease:a consensus summary from the alli⁃ ance of investigators on calcific aortic valve disease[J].Arterioscler Thromb Vasc Biol,2014,34(11):2387-2393

    • [65] YU C,LI L,XIE F,et al.LncRNA TUG1 sponges miR ⁃ 204 ⁃ 5p to promote osteoblast differentiation through up⁃ regulating Runx2 in aortic valve calcification[J].Cardio⁃ vasc Res,2018,114(1):168-179

    • [66] XIAO X,ZHOU T,GUO S,et al.LncRNA MALAT1 sponges miR ⁃204 to promote osteoblast differentiation of human aortic valve interstitial cells through up⁃regulating Smad4[J].Int J Cardiol,2017,243:404-412

    • [67] HE W,LI F,ZHANG S,et al.LncRNA AFAP1⁃AS1 pro⁃ motes osteoblast differentiation of human aortic valve in⁃ terstitial cells through regulating miR ⁃ 155/SMAD5 axis [J].Mol Cell Probes,2020,50:101509

  • 通知关闭
    郑重声明