Abstract
microRNAs (miRNAs) are an evolutionarily conserved class of small single-stranded noncoding RNAs. The aberrant expression of specific miRNAs has been implicated in the development and progression of diverse cardiovascular diseases. For many decades, miRNA therapeutics has flourished, taking advantage of the fact that miRNAs can modulate gene expression and control cellular phenotypes at the posttranscriptional level. Genetic replacement or knockdown of target miRNAs by chemical molecules, referred to as miRNA mimics or inhibitors, has been used to reverse their abnormal expression as well as their adverse biological effects in vitro and in vivo in an effort to fully implement the therapeutic potential of miRNA-targeting treatment. However, the limitations of the chemical structure and delivery systems are hindering progress towards clinical translation. Here, we focus on the regulatory mechanisms and therapeutic trials of several representative miRNAs in the context of specific cardiovascular diseases; from this basic perspective, we evaluate chemical modifications and delivery vectors of miRNA-based chemical molecules and consider the underlying challenges of miRNA therapeutics as well as the clinical perspectives on their applications.
Keywords: microRNAs, Cardiovascular disease, Antisense oligonucleotides, miRNA therapeutics, Drug discovery, Chemical modification, Drug delivery systems, Gene therapy.
[http://dx.doi.org/10.1161/CIR.0000000000000659] [PMID: 30700139]
[http://dx.doi.org/10.3389/fgene.2015.00002] [PMID: 25674102]
[http://dx.doi.org/10.3389/fgene.2019.00057] [PMID: 30853970]
[http://dx.doi.org/10.3389/fpls.2015.01001] [PMID: 26635829]
[http://dx.doi.org/10.1038/nrd4018] [PMID: 23722346]
[http://dx.doi.org/10.1038/nature05874] [PMID: 17571346]
[http://dx.doi.org/10.1038/nature03001] [PMID: 15496913]
[http://dx.doi.org/10.1038/nrg3965] [PMID: 26077373]
[http://dx.doi.org/10.1038/nrd.2016.246] [PMID: 28209991]
[http://dx.doi.org/10.1038/nrd3864] [PMID: 23080337]
[http://dx.doi.org/10.1038/mt.2015.133] [PMID: 26216517]
[http://dx.doi.org/ 10.3978/j.issn.2223-3652.2014.12.03] [PMID: 25774345]
[http://dx.doi.org/10.1073/pnas.0608791103] [PMID: 17108080]
[http://dx.doi.org/10.1056/NEJMoa1209026] [PMID: 23534542]
[http://dx.doi.org/10.4155/fmc.15.107] [PMID: 26399457]
[http://dx.doi.org/10.1016/j.canlet.2017.04.007] [PMID: 28412239]
[http://dx.doi.org/10.1016/0092-8674(93)90529-Y] [PMID: 8252621]
[http://dx.doi.org/10.1038/35002607] [PMID: 10706289]
[http://dx.doi.org/10.1016/j.cell.2004.12.031] [PMID: 15652478]
[http://dx.doi.org/10.15252/emmm.201100899] [PMID: 24935956]
[http://dx.doi.org/10.1038/sj.emboj.7600385] [PMID: 15372072]
[http://dx.doi.org/10.1038/nsmb1167] [PMID: 17099701]
[http://dx.doi.org/10.1101/gad.1262504] [PMID: 15574589]
[http://dx.doi.org/10.1016/j.cell.2006.03.043] [PMID: 16751099]
[http://dx.doi.org/10.1038/nature05983] [PMID: 17589500]
[http://dx.doi.org/10.1101/gad.1158803] [PMID: 14681208]
[http://dx.doi.org/10.1038/nature03868] [PMID: 15973356]
[http://dx.doi.org/10.1016/j.cell.2005.10.022] [PMID: 16271387]
[http://dx.doi.org/10.1016/j.cell.2007.10.032] [PMID: 18083100]
[http://dx.doi.org/10.1038/ncb0309-228] [PMID: 19255566]
[http://dx.doi.org/10.1016/j.cell.2009.01.002] [PMID: 19167326]
[http://dx.doi.org/10.1038/nrg2843] [PMID: 20661255]
[http://dx.doi.org/10.1038/nrg2936] [PMID: 21245828]
[http://dx.doi.org/10.1093/hmg/ddq367]
[http://dx.doi.org/10.1126/science.1181046] [PMID: 20007902]
[http://dx.doi.org/10.1016/j.bbrc.2015.07.160] [PMID: 26253469]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.113.001904] [PMID: 23897866]
[http://dx.doi.org/10.1126/science.1178178] [PMID: 19965718]
[http://dx.doi.org/10.1038/ncb1596] [PMID: 17486113]
[http://dx.doi.org/10.1038/cr.2008.282] [PMID: 18766170]
[http://dx.doi.org/10.1038/ncb2210] [PMID: 21423178]
[http://dx.doi.org/10.1073/pnas.1019055108] [PMID: 21383194]
[http://dx.doi.org/10.1373/clinchem.2010.147405] [PMID: 20847327]
[http://dx.doi.org/10.1093/eurheartj/ehv321] [PMID: 26206211]
[http://dx.doi.org/10.1111/j.1440-1827.2010.02526.x] [PMID: 20518884]
[http://dx.doi.org/10.1161/CIRCRESAHA.114.302213] [PMID: 24255059]
[http://dx.doi.org/10.2310/JIM.0b013e3181ff46d7] [PMID: 21030878]
[http://dx.doi.org/10.1155/2016/8060182] [PMID: 27843203]
[http://dx.doi.org/10.1016/j.yjmcc.2016.03.015] [PMID: 27056419]
[http://dx.doi.org/10.1038/nature03817] [PMID: 15951802]
[http://dx.doi.org/10.1002/wsbm.111] [PMID: 21305703]
[http://dx.doi.org/10.1172/JCI36154] [PMID: 19726871]
[http://dx.doi.org/10.1073/pnas.1208863110] [PMID: 23248315]
[http://dx.doi.org/10.1667/RR13784.1] [PMID: 25594541]
[http://dx.doi.org/10.1161/CIRCRESAHA.111.248880] [PMID: 21778430]
[http://dx.doi.org/10.1136/jim-2017-000485] [PMID: 28814571]
[http://dx.doi.org/10.1002/ddr.21257] [PMID: 26082192]
[http://dx.doi.org/10.1016/j.ejca.2015.04.006] [PMID: 26002251]
[http://dx.doi.org/10.1186/s12872-017-0520-7] [PMID: 28335740]
[http://dx.doi.org/10.1159/000479995] [PMID: 28817807]
[http://dx.doi.org/10.1093/cvr/cvu254] [PMID: 25504627]
[http://dx.doi.org/10.1172/JCI43604] [PMID: 20978354]
[http://dx.doi.org/10.1016/j.yexcr.2013.12.025] [PMID: 24394541]
[http://dx.doi.org/10.1161/CIRCRESAHA.114.303125] [PMID: 24481837]
[http://dx.doi.org/10.1093/cvr/cvu162] [PMID: 25020912]
[http://dx.doi.org/10.1161/JAHA.114.000946] [PMID: 25240056]
[http://dx.doi.org/10.1016/j.yexmp.2013.12.004] [PMID: 24368110]
[http://dx.doi.org/10.1073/pnas.0905063106] [PMID: 19843690]
[http://dx.doi.org/10.1016/j.bbrc.2017.12.001] [PMID: 29203244]
[http://dx.doi.org/10.1016/j.devcel.2008.07.008] [PMID: 18694566]
[http://dx.doi.org/10.1111/imr.12042] [PMID: 23550635]
[http://dx.doi.org/10.1111/imr.12057] [PMID: 23550644]
[http://dx.doi.org/10.1038/srep22613] [PMID: 26931072]
[http://dx.doi.org/10.1161/ATVBAHA.114.304723] [PMID: 25810298]
[http://dx.doi.org/10.1161/CIRCRESAHA.114.303784] [PMID: 24657879]
[http://dx.doi.org/10.1517/14728222.2016.1164693] [PMID: 26959615]
[http://dx.doi.org/10.1186/gm272] [PMID: 21888691]
[http://dx.doi.org/10.1002/jcb.24075] [PMID: 22275134]
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.10094] [PMID: 29255073]
[http://dx.doi.org/10.1159/000447853] [PMID: 27614440]
[http://dx.doi.org/10.1161/01.RES.0000257913.42552.23] [PMID: 17234972]
[http://dx.doi.org/10.1161/JAHA.113.000078] [PMID: 23612897]
[http://dx.doi.org/10.1242/jcs.067165] [PMID: 20571053]
[http://dx.doi.org/10.1128/MCB.01222-08] [PMID: 19188439]
[http://dx.doi.org/10.1093/cvr/cvs196] [PMID: 22719074]
[http://dx.doi.org/10.1111/j.1582-4934.2011.01307.x] [PMID: 21418519]
[http://dx.doi.org/10.2353/ajpath.2007.061170] [PMID: 17525252]
[http://dx.doi.org/10.1038/nature07511] [PMID: 19043405]
[http://dx.doi.org/10.1172/JCI70577] [PMID: 24743145]
[http://dx.doi.org/10.1038/mt.2016.166] [PMID: 27545313]
[http://dx.doi.org/10.1038/nm1582] [PMID: 17468766]
[http://dx.doi.org/10.1161/CIRCRESAHA.108.182535] [PMID: 19096030]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.111.030932] [PMID: 21900086]
[http://dx.doi.org/10.1161/CIRCRESAHA.115.303910] [PMID: 25287062]
[http://dx.doi.org/10.1134/S0006297914060078] [PMID: 25100012]
[http://dx.doi.org/10.1371/journal.pone.0041574] [PMID: 22844503]
[http://dx.doi.org/10.1371/journal.pone.0168078] [PMID: 27992564]
[http://dx.doi.org/10.1111/jcmm.12445] [PMID: 25583328]
[http://dx.doi.org/10.1093/cvr/cvu184] [PMID: 25103110]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.112.001357] [PMID: 23956210]
[http://dx.doi.org/10.1016/j.ymthe.2016.09.001] [PMID: 28129114]
[http://dx.doi.org/10.1177/1074248415616188] [PMID: 26589288]
[http://dx.doi.org/10.1016/j.yjmcc.2011.07.001] [PMID: 21771600]
[http://dx.doi.org/10.1016/j.cmet.2015.02.014] [PMID: 25863248]
[http://dx.doi.org/10.1016/j.heliyon.2018.e00639] [PMID: 30009269]
[http://dx.doi.org/10.1038/cdd.2014.187] [PMID: 25394488]
[http://dx.doi.org/10.1161/CIRCGENETICS.110.958975] [PMID: 21642241]
[http://dx.doi.org/10.1186/1423-0127-18-22] [PMID: 21406115]
[http://dx.doi.org/10.1536/ihj.50.377] [PMID: 19506341]
[http://dx.doi.org/10.12659/MSM.897266] [PMID: 27411964]
[http://dx.doi.org/10.1126/science.1174381] [PMID: 19460962]
[http://dx.doi.org/10.1016/j.devcel.2008.07.002] [PMID: 18694565]
[http://dx.doi.org/10.1016/j.ijcard.2013.01.160] [PMID: 23465244]
[http://dx.doi.org/10.1007/s11010-014-2239-4] [PMID: 25318608]
[http://dx.doi.org/10.1016/j.gene.2018.12.044] [PMID: 30597234]
[http://dx.doi.org/10.3892/ijmm.2012.1200] [PMID: 23229021]
[http://dx.doi.org/10.1159/000485949] [PMID: 29241208]
[http://dx.doi.org/10.1007/s11010-017-2990-4] [PMID: 28283792]
[http://dx.doi.org/10.1159/000447825] [PMID: 27577116]
[http://dx.doi.org/10.1016/j.biopha.2018.07.141] [PMID: 30119250]
[http://dx.doi.org/10.1536/ihj.17-147] [PMID: 29681568]
[http://dx.doi.org/10.1093/eurjhf/hfs143] [PMID: 22941949]
[http://dx.doi.org/10.1159/000484588] [PMID: 29131009]
[http://dx.doi.org/10.1159/000452506] [PMID: 27832626]
[http://dx.doi.org/10.1038/nm.2282] [PMID: 21186368]
[http://dx.doi.org/10.4161/rna.28300] [PMID: 24646523]
[http://dx.doi.org/10.1371/journal.pone.0019481] [PMID: 21573063]
[http://dx.doi.org/10.1371/journal.pone.0060161] [PMID: 23560074]
[http://dx.doi.org/10.1038/nature08899] [PMID: 20336145]
[http://dx.doi.org/10.18632/aging.100526] [PMID: 23425860]
[http://dx.doi.org/10.1161/CIRCRESAHA.111.244442] [PMID: 22052914]
[http://dx.doi.org/10.7150/ijbs.15071] [PMID: 27489501]
[http://dx.doi.org/10.1093/cvr/cvr145] [PMID: 21622680]
[http://dx.doi.org/10.1016/j.biopha.2018.04.181] [PMID: 29852387]
[http://dx.doi.org/10.18632/oncotarget.15391]
[http://dx.doi.org/10.1152/physiolgenomics.00020.2014] [PMID: 25159851]
[http://dx.doi.org/10.1016/j.biocel.2012.08.019] [PMID: 22960625]
[http://dx.doi.org/10.1093/cvr/cvp015] [PMID: 19147652]
[http://dx.doi.org/10.1111/1755-5922.12118] [PMID: 25809568]
[http://dx.doi.org/10.12659/MSM.897773] [PMID: 27708252]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.116.022478] [PMID: 27780851]
[http://dx.doi.org/10.1038/nm.3487] [PMID: 24584117]
[http://dx.doi.org/10.1073/pnas.0707493105] [PMID: 18227515]
[http://dx.doi.org/10.1159/000484236] [PMID: 29316562]
[http://dx.doi.org/10.1371/journal.pone.0046551] [PMID: 23189122]
[http://dx.doi.org/10.1016/j.biopha.2018.05.068] [PMID: 29803178]
[http://dx.doi.org/10.1093/cvr/cvu070] [PMID: 24675724]
[http://dx.doi.org/10.1172/JCI61716] [PMID: 23041630]
[http://dx.doi.org/10.1161/CIRCRESAHA.108.185363] [PMID: 19150885]
[http://dx.doi.org/10.1007/s11010-014-2211-3] [PMID: 25893733]
[http://dx.doi.org/10.1016/j.bbrc.2012.12.157] [PMID: 23333386]
[http://dx.doi.org/10.1161/ATVBAHA.110.206201] [PMID: 20489169]
[http://dx.doi.org/10.1128/MCB.01237-09] [PMID: 20516212]
[http://dx.doi.org/10.1016/j.gene.2015.04.014] [PMID: 25865302]
[http://dx.doi.org/10.1016/j.atherosclerosis.2010.12.024] [PMID: 21310411]
[http://dx.doi.org/10.1016/j.atherosclerosis.2015.06.031] [PMID: 26117405]
[http://dx.doi.org/10.1002/cbf.3005] [PMID: 24604335]
[http://dx.doi.org/10.1038/nm1569] [PMID: 17401374]
[http://dx.doi.org/10.1371/journal.pone.0085639] [PMID: 24386485]
[http://dx.doi.org/10.1161/CIRCEP.114.002162] [PMID: 25995211]
[http://dx.doi.org/10.1161/CIRCRESAHA.108.181651] [PMID: 19131648]
[http://dx.doi.org/10.1093/eurheartj/ehs043] [PMID: 22362515]
[http://dx.doi.org/10.1016/j.ijcard.2012.07.009] [PMID: 22889704]
[http://dx.doi.org/10.1371/journal.pone.0028324] [PMID: 22163007]
[http://dx.doi.org/10.1016/j.hrthm.2013.03.005] [PMID: 23499625]
[http://dx.doi.org/10.1016/j.bbacli.2017.02.002] [PMID: 28239561]
[http://dx.doi.org/10.1161/CIRCRESAHA.112.267443] [PMID: 22715471]
[http://dx.doi.org/10.1038/nrneurol.2017.148] [PMID: 29192260]
[http://dx.doi.org/10.1016/j.chembiol.2012.07.011] [PMID: 22921062]
[http://dx.doi.org/10.1080/15476286.2018.1445959] [PMID: 29570036]
[http://dx.doi.org/10.1016/S0167-4781(99)00140-2] [PMID: 10806998]
[http://dx.doi.org/10.1089/oli.1.2000.10.117] [PMID: 10805163]
[http://dx.doi.org/10.1038/nature04303] [PMID: 16258535]
[http://dx.doi.org/10.1146/annurev.pharmtox.010909.105654] [PMID: 20055705]
[http://dx.doi.org/10.1038/mtna.2015.23] [PMID: 26372022]
[http://dx.doi.org/10.1111/j.1440-1681.2006.04403.x] [PMID: 16700890]
[http://dx.doi.org/10.1371/journal.pbio.0020098] [PMID: 15024405]
[http://dx.doi.org/10.1016/j.cmet.2006.01.005] [PMID: 16459310]
[http://dx.doi.org/10.1093/nar/gkn904] [PMID: 19015151]
[http://dx.doi.org/10.1038/nature06783] [PMID: 18368051]
[http://dx.doi.org/10.1038/cgt.2016.25] [PMID: 27364574]
[http://dx.doi.org/10.1016/S1074-5521(00)00058-2] [PMID: 11182314]
[http://dx.doi.org/10.1038/ng.786] [PMID: 21423181]
[http://dx.doi.org/10.1093/nar/gkl175] [PMID: 16670427]
[http://dx.doi.org/10.1089/oli.1.1997.7.187] [PMID: 9212909]
[http://dx.doi.org/10.1073/pnas.92.13.5798]
[http://dx.doi.org/10.1038/gt.2011.100] [PMID: 21753793]
[http://dx.doi.org/10.1002/jctb.1505]
[http://dx.doi.org/10.1016/j.pharmthera.2015.07.003] [PMID: 26210404]
[http://dx.doi.org/10.1038/mtna.2013.46] [PMID: 23982190]
[http://dx.doi.org/10.1093/nar/gkf412] [PMID: 12087157]
[http://dx.doi.org/10.1089/oli.2006.0046] [PMID: 17461763]
[http://dx.doi.org/10.1093/nar/gkh187] [PMID: 14726483]
[http://dx.doi.org/10.1038/sj.gt.3302313] [PMID: 15229633]
[http://dx.doi.org/10.1016/j.addr.2007.03.007] [PMID: 17462786]
[http://dx.doi.org/10.1016/j.addr.2014.05.009] [PMID: 24859533]
[http://dx.doi.org/10.1146/annurev-neuro-080317-062048] [PMID: 29709207]
[http://dx.doi.org/10.1038/nm.2791] [PMID: 22660636]
[http://dx.doi.org/10.3390/biomedicines1010003] [PMID: 28548054]
[http://dx.doi.org/10.1038/mt.2008.76] [PMID: 18414476]
[http://dx.doi.org/10.1016/j.cardfail.2008.02.005] [PMID: 18514926]
[http://dx.doi.org/10.1016/j.ijpharm.2013.01.050] [PMID: 23380621]
[http://dx.doi.org/10.1007/s11095-012-0874-6] [PMID: 22983644]
[http://dx.doi.org/10.1158/2159-8290.CD-13-0159] [PMID: 24002999]
[http://dx.doi.org/10.1073/pnas.1418401112] [PMID: 25713383]
[http://dx.doi.org/10.3390/ht6040013] [PMID: 29485611]
[http://dx.doi.org/10.1016/j.biomaterials.2012.10.023] [PMID: 23111335]
[http://dx.doi.org/10.1021/nl9003865] [PMID: 19331425]
[http://dx.doi.org/10.1021/nl500844m] [PMID: 24689438]
[http://dx.doi.org/10.1039/c2nr31290e] [PMID: 22782309]
[http://dx.doi.org/10.1016/j.addr.2008.02.012] [PMID: 18448187]
[http://dx.doi.org/10.4103/2230-973X.108958] [PMID: 23799200]
[http://dx.doi.org/10.1038/nature13905] [PMID: 25409146]
[http://dx.doi.org/10.1016/B978-0-12-800148-6.00009-2] [PMID: 25409609]
[http://dx.doi.org/10.1021/mp800051m] [PMID: 18672949]
[http://dx.doi.org/10.1016/j.jconrel.2013.08.005] [PMID: 23965281]
[http://dx.doi.org/10.1016/j.progpolymsci.2007.05.001]
[http://dx.doi.org/10.1021/ja505986a] [PMID: 25434769]
[http://dx.doi.org/10.1093/nar/gku531] [PMID: 24992960]
[http://dx.doi.org/10.1038/nrm3838] [PMID: 25027649]