De Palma, Michele

Squadrito, Mario Leonardo

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EDITORIALMicromanaging restenosis by therapeutic inhibitionof miR-92aMario Leonardo Squadrito and Michele De Palma*Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, E´cole Polytechnique Fe´de´rale de Lausanne (EPFL), Lausanne 1015, SwitzerlandOnline publish-ahead-of-print 31 July 2014This editorial refers to ‘Inhibition of miR-92a improvesre-endothelialization and prevents neointima formation fol-lowing vascular injury’ by J.-M. Daniel et al., pp. 564–572, thisissue.The adverse consequences of procedure-associated endovascularinjury may limit the long-term benefits of coronary interventions likeangioplasty and stent insertion. Damage to the artery’s endotheliumand impaired re-endothelialization, also caused by the use of non-selective anti-proliferative drugs, may promote the development of re-stenosis—a pathological condition characterized by smooth muscle cell(SMC) hyperplasia, vessel thickening and lumen narrowing, and impairedblood flow—in a significant proportion of the patients. Reducing theoccurrence of restenosis after coronary interventions thus remains animportant medical need.1 In this issue of Cardiovascular Research,Daniel et al. 2 report that both genetic and molecular (therapeutic)approaches to inhibit microRNA (miRNA)-92a facilitate arterial re-endothelialization and prevent restenosis in a mouse model of femoralartery injury.miRNAs are a class of small non-coding RNAs that fine-tune gene ex-pression at the post-transcriptional level. Several miRNAs, includingmiR-126, miR-132, miR-222, and miR-92a, have been implicated in theregulation of endothelial cell (EC) biology.3 miR-92a is a member ofthe miR-17-92 cluster, which encodes six distinct miRNAs broadlyinvolved in physiological and pathological processes such as cell prolifer-ation, development, immunity, and tumorigenesis.4 While being deregu-lated in several leukaemias and solid tumours, miR-92a also functions as anegative regulator of EC proliferation, angiogenesis, and vascular repair.Therapeutic modulation of miR-92a activity in ECs may, therefore,rescue the damaged endothelium after coronary interventions.5– 8Daniel et al.2 employed a mouse model of wire-induced injury of thefemoral artery to analyse the temporal and cellular expression ofmiR-92a after vascular damage. They found that miR-92a levelsincreased post-injury and peaked at Day 10, a time-point when SMChyperplasia was already evident in the injured artery. The analysis of cul-tured ECs and SMCs, as well as intact or endothelium-denudated arter-ies, suggested thatECsandnotSMCs were themain sourceofmiR-92a inthe injured arteries. Moreover, transfection of miR-92a inhibitedvascular endothelial growth factor-A (VEGFA)-induced EC proliferationand migration, but did not affect platelet-derived growth factor-BB(PDGFB)-induced SMC proliferation or migration, indicating that thefunctions of miR-92a are largely EC-autonomous. The authors thenused two loss-of-function strategies to attenuate miR-92a activity inthe damaged arteries. Both the systemic delivery of locked nucleicacid (LNA)-modified anti-miR-92a oligonucleotides9 and the condition-al knockout of miR-92a in TIE2+ ECs stimulated re-endothelializationand decreased SMC hyperplasia and inflammatory–macrophage infiltra-tion in the femoral artery after wire-induced injury (Figure 1). These datasuggest that suppression of endothelial miR-92a activity promotes arter-ial re-endothelialization and limits SMC hyperplasia, at least in part,through direct pro-proliferative effects on ECs.2 Consistent with thesefindings, previous studies showed that inhibition of miR-92a enhancesVEGFA-induced EC proliferation by activating mitogenic ERK and JNKsignalling.6Besides direct pro-proliferative effects on ECs, inhibition of miR-92amay attenuate experimental restenosis through additional mechanisms.Among the validated targets of miR-92a are the deacetylase sirtuin-1(Sirt1) and integrin-a5 (Itga5). SIRT1 is highlyexpressed in the angiogenicvasculature and promotes sprouting angiogenesis, whereas ITGA5enables migration, pro-angiogenic signalling, and angiogenesis of ECsby modulating their interactions with the extra-cellular matrix.10Daniel et al.2 observed increased expression of both SIRT1 andITGA5 in the arterial ECs of anti-miR-92a–treated mice 2 weekspost-injury, suggesting that therapeutic inhibition of miR-92a stimulatesre-endothelialization, at least in part, by de-repressing both pro-angiogenic factors. miR-92a also targets the transcription factorsKru¨ppel-like factor-2 (KLF2) and 4,11 which confer anti-inflammatoryand atheroprotective properties to the endothelium. De-repressedKLF2 and 4 may operate to down-regulate the expression of leucocyteadhesion molecules on ECs, hence limiting inflammatory cell infiltration,and to enhance endothelial nitric oxide (NO) synthetase (NOS3/eNOS) activity, which inhibits SMC proliferation through NO pro-duction.6,11,12 Thus, therapeutic inhibition of miR-92a may initiate ananti-atherosclerotic programme in ECs that limits inflammatory cellinfiltration and SMC proliferation in the healing arteries.5 –8Daniel et al.2 andprevious studies5 –8 employedanti-miR-92a oligonu-cleotides delivered systemically in animal models of vascular injury.The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology.* Corresponding author. Tel: +41 21 6937271, Email: michele.depalma@epfl.chPublished on behalf of the European Society of Cardiology. All rights reserved.& The Author 2014. For permissions please email: journals.permissions@oup.com.Cardiovascular Research (2014) 103, 432–434doi:10.1093/cvr/cvu178Because systemic anti-miR oligonucleotides target multiple organs andcell types,9,13 this approach may have altered miR-92a activity also innon-ECs. Furthermore, anti-miR-92a oligonucleotides may potentiallytarget several mature miRNAs. Indeed, miR-92a, miR-92b, and miR-25belong to the same miRNA family and thus share the seed-sequenceused to design anti-miR oligonucleotides. Moreover, two maturemiR-92a sequences exist that are expressed from two distinct geneticloci, miR-17-92 (encoding miR-92a-1) and miR-106-363 (encodingmiR-92a-2). Based on the above, non-EC autonomous effects and po-tential co-targeting of distinct miRNA species could not be formallyexcluded in previous studies.5– 8 To address these issues, Daniel et al.2employed conditional knockout strategies either targeting themiR-92a-1 gene broadly in haematopoietic cells or specifically in TIE2-lineage cells, which comprise both ECs and haematopoietic cells.14 Bythis comparative analysis, the authors unequivocally showed that themiR-92a sequence encoded by the miR-17-92 locus is functionally im-portant in the endothelial, but not in the haematopoietic, lineage.Although not yetbroadly tested in theclinic, anti-miR therapeutics arebeing successfully used in animal models to experimentally suppress miRactivity.9,13 For example, systemic anti-miR-33 therapy holds promisefor the treatment of dyslipidaemias and associated vascular/cardiac dis-eases, as shown by preclinical studies in animal models.13 Remarkably, aphase II clinical study recently demonstrated the efficacy of a LNA-modified anti-miR-122 for the inhibition of hepatitis C virus (HCV) rep-lication in patients.15 It should be noted that both the pharmacokineticproperties and the intravenous route of administration of anti-miRs fa-cilitate targeting of the liver, which may explain the reported successof anti-miR-122/33–based treatments in animal models and patients.13On the other hand, it is currently unclear whether systemic administra-tion of anti-miR-92a therapeutics would efficiently target the arterialFigure1 Inhibition of restenosis by therapeutic or genetic miR-92a targeting. Endothelial damage consequent to coronary interventions (A) up-regulatesthe expression of miR-92a, which directly targets the pro-angiogenic and anti-inflammatory factors Sirt1, Itga5, and Klf2/4 (B), inhibits EC proliferation, andpromotes the development of restenosis (C). Systemic treatment with anti-miR-92a oligonucleotides (D), or the genetic deletion of miR-92a in ECs (E),restores Sirt1, Itga5, and Klf2/4 levels in the healing endothelium, stimulates re-endothelialization, decreases SMC hyperplasia (via increased eNOS activityand NO production), and ultimately limits the development of restenosis (F ). Please see text for references.Editorial 433endothelium of patients undergoing coronary interventions. Also, po-tential toxicities associated with the systemic down-regulation ofmiR-92a, particularly in non-ECs, should be considered. AlthoughmiR-92a knockout mice are viable and fertile, they show increased em-bryonic lethality as well as growth and skeletal defects.16 To alleviatethese concerns, drug-eluting stents1 that deliver anti-miR-92a locallyto the healing endothelium should be tested in large animal models toexplore the advantages and disadvantages of this approach comparedwith systemic administration.Conflict of interest: none declared.FundingWork in the authors’ laboratory is, in part, funded by the European ResearchCouncil (ERC TIE2+ monocytes) and Fonds National Suisse de la Recher-che Scientifique (SNSF grant 31003A-143978).References1. StefaniniGG, Holmes DR Jr. Drug-eluting coronary-artery stents.NEngl JMed2013;368:254–265.2. Daniel JM, Penzkofer D, Teske R, Dutzmann J, Koch A, Bielenberg W, Bonauer A,Boon RA, Fischer A, Bauersachs J, van Rooij E, Dimmeler S, Sedding DG. Inhibition ofmir-92a improves re-endothelialization and preventsneointima formation following vas-cular injury. Cardiovasc Res 2014;103:564–572.3. Anand S, Cheresh DA. MicroRNA-mediated regulation of the angiogenic switch. CurrOpin Hematol 2011;18:171–176.4. Mogilyansky E,Rigoutsos I. Themir-17/92cluster: acomprehensiveupdateon its genom-ics, genetics, functions and increasingly important and numerous roles in health anddisease. Cell Death Differ 2013;20:1603–1614.5. Bonauer A, Carmona G, Iwasaki M, Mione M, Koyanagi M, Fischer A, Burchfield J, Fox H,Doebele C, Ohtani K, Chavakis E, Potente M, Tjwa M, Urbich C, Zeiher AM, Dimmeler S.MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues inmice. Science 2009;324:1710–1713.6. Iaconetti C, Polimeni A, Sorrentino S, Sabatino J, Pironti G, Esposito G, Curcio A,Indolfi C. Inhibition of mir-92a increases endothelial proliferation and migration invitro as well as reduces neointimal proliferation in vivo after vascular injury. Basic ResCardiol 2012;107:296.7. Hinkel R, Penzkofer D, Zuhlke S, Fischer A, Husada W, Xu QF, Baloch E, van Rooij E,Zeiher AM, Kupatt C, Dimmeler S. Inhibition of microRNA-92a protects against ische-mia/reperfusion injury in a large-animal model. Circulation 2013;128:1066–1075.8. Loyer X, Potteaux S, Vion AC, Guerin CL, Boulkroun S, Rautou PE, Ramkhelawon B,Esposito B, Dalloz M, Paul JL, Julia P, Maccario J, Boulanger CM, Mallat Z, Tedgui A. Inhib-ition of microRNA-92a prevents endothelial dysfunction and atherosclerosis in mice.Circ Res 2014;114:434–443.9. Lennox KA, Behlke MA. Chemical modification and design of anti-miRNA oligonucleo-tides. Gene Ther 2011;18:1111–1120.10. Potente M, Gerhardt H, Carmeliet P. Basic and therapeutic aspects of angiogenesis. Cell2011;146:873–887.11. Fang Y, Davies PF. Site-specific microRNA-92a regulation of Kruppel-like factors 4 and 2in atherosusceptible endothelium. Arterioscler Thromb Vasc Biol 2012;32:979–987.12. Hamik A, Lin Z, Kumar A, Balcells M, Sinha S, Katz J, Feinberg MW, Gerzsten RE,Edelman ER, Jain MK. Kruppel-like factor 4 regulates endothelial inflammation. The JBiol Chem 2007;282:13769–13779.13. van Rooij E, Purcell AL, Levin AA. Developing microRNA therapeutics. Circ Res 2012;110:496–507.14. De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, Naldini L. Tie2identifies a hematopoietic lineage of proangiogenic monocytes required for tumorvessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell2005;8:211–226.15. Janssen HL, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, van derMeer AJ, Patick AK, Chen A, Zhou Y, Persson R, King BD, Kauppinen S, Levin AA,Hodges MR. Treatment of HCV infection by targeting microRNA. N Engl J Med 2013;368:1685–1694.16. Penzkofer D, Bonauer A, Fischer A, Tups A, BrandesRP, Zeiher AM, Dimmeler S. Pheno-typic characterization of mir-92a2/2 mice reveals an important function of mir-92a inskeletal development. PLoS ONE 2014;9:e101153.Editorial434

Micromanaging restenosis by therapeutic inhibition of miR-92a

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