the management of cardiovascular risk through epigenetic … · 2019. 5. 12. · 4...

Review ArticleThe Management of Cardiovascular Risk throughEpigenetic Biomarkers

Laurent Metzinger1 Stefano de Franciscis23 and Raffaele Serra23

1CURS Laboratoire INSERM U1088 Universite de Picardie Jules Verne chemin duThil 80025 Amiens Cedex 1 France2Interuniversity Center of Phlebolymphology (CIFL) International Research and Educational Program in Clinical andExperimental Biotechnology University Magna Graecia of Catanzaro Viale Europa 88100 Catanzaro Italy3Department of Medical and Surgical Sciences University Magna Graecia of Catanzaro Viale Europa 88100 Catanzaro Italy

Correspondence should be addressed to Raffaele Serra rserrauniczit

Received 21 December 2016 Accepted 15 June 2017 Published 13 July 2017

Academic Editor Klaus Wimmers

Copyright copy 2017 Laurent Metzinger et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Epigenetic sciences study heritable changes in gene expression not related to changes in the genomic DNA sequence The mostimportant epigenetic mechanisms are DNAmethylation posttranslational histonemodification and gene regulation by noncodingRNAs such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) Cardiovascular diseases (CVD) are responsible forat least one-third of premature deaths worldwide and represent a heavy burden of healthcare expenditure We will discuss inthis review the most recent findings dealing with epigenetic alterations linked to cardiovascular physiopathology in patients Aparticular focus will be put on the way these changes can be translated in the clinic to develop innovative and groundbreakingbiomarkers in CVD field

1 Introduction

Epigenetics is the study of all the heritable changes in geneexpression that do not involve changes to genomic DNAsequences in themselves Epigenetic mechanisms represent astable cellular memory that allows the propagation of geneactivities from one generation of cells to another The threemain epigenetic processes are represented by DNA methy-lation posttranslational histone modifications and RNA-based mechanisms such as noncoding RNAs representedmainly bymicroRNAs (miRNAs) and long noncoding RNAs(lncRNAs) [1 2]

Cardiovascular diseases (CVD) are responsible for one-third of all deathsworldwide and accounting for an importantburden of healthcare expenditure Previously epigeneticmodificationswere reported to play a pivotal role in processesunderlying CVD including atherosclerosis inflammationand hypertension [3] To date most of the limitations forthe full understanding of the genetic influence on cardiovas-cular diseases (CVD) are probably due to the static simpleevaluation of the DNA code In this context epigenetics

through the study of several dynamic pathways modifyalso the genomersquos functionality under exogenous influencewhich could identify novel mechanisms and targets in thecontrol of gene regulation with significant acquisitions inCVD knowledge of its genetic risk and pathophysiology [1ndash3] Indeed epigenetic modifications such as histones modifi-cations DNAmethylation and small noncoding RNAs occurin response to environmental changes Pollution and diet willprofoundly change these epigeneticmodifications and triggersusceptibility to CVD For example as will also be discussedin this review DNA methylation has been associated withatherosclerosis [4] abdominal aortic aneurysm [5] andcoronary heart disease [6]

This review will thus focus on the role of the mainmechanisms of epigenetics in the area of cardiovascular risk

2 Literature Search

In the context of CVD we decided to search for relevantarticles in the three main areas of interest of epigeneticsDNA methylation posttranslational histone modifications

HindawiBioMed Research InternationalVolume 2017 Article ID 9158572 6 pageshttpsdoiorg10115520179158572

2 BioMed Research International

and RNA-based mechanisms PubMed Scopus and Sci-ence Direct databases were used for the search strategy APubMed search using the terms cardiovascular + epigenetic+ biomarker found 261 results in May 2017

3 DNA Methylation

DNA methylation partly controlled by DNA methyltrans-ferases is usually associated with transcriptional repressionwhile demethylation is associated with transcriptional activa-tion influencing gene expression by altering DNA promoteraccessibility to RNA polymerase and consequently genetranscription [7] A PubMed search using the terms cardio-vascular + methylation + biomarker + biomarker found 185results in May 2017

In this context the concept of globalmethylation refers tothe overall level of methylcytosines in the genome expressedas percentage of total cytosines In fact a large proportionof methylation sites within the genome are found in repeatsequences and transposable elements such as Alu and long-interspersed nuclear element (LINE-1) and this correlateswith the total genomic methylation content and for thisreason LINE-1 is used as a surrogate for the overall methy-lation of the genome [3] Interestingly LINE-1 methylation isincreased in males [21] while it is not affected by either ageor natural cycle of hormones

Several research teams have studied the possibility thatDNA methylation could be correlated with the risk of CVDSeveral evidences showed that global DNA methylationassessed at LINE-1 sequences was inversely and indepen-dently related to CVD risk thus more proportions of globalDNA methylation are indicative of a higher CVD risk [3 2223] Very recently a Swedish team performed an epigenome-wide association study to identify disease-specific alterationsin DNA methylation in blood samples of a Swedish popula-tion of 729 patients afflicted with hypertension myocardialinfarction stroke thrombosis and cardiac arrhythmia [24]

For this they used an Illumina Infinium BeadChipDifferential DNAmethylation was detected inmore than 200CpG-sites in patients with a history of myocardial infarctionAmong these sites 42 genes were related to cardiac functionThe authors concluded that individuals with a history of MIhave an altered pattern of DNA methylation at numerousgenomic loci linked to CVD These sites are thus potentialbiomarkers for CVD [24] DNAmethylation in specific genescan also be helpful to predict response to a specific treatmentTwo elegant studies by Gallego-Fabrega et al have shownthat changes in DNA methylation patterns of PPM1A andTRAF3 are respectively associated with vascular recurrencein aspirin-treated patients and clopidogrel response andrecurrence of ischemic events in patients with stroke [25 26]

4 Posttranslational Histone Modifications

Eukaryotic DNA is wrapped around an octamer of thecore histones that build the fundamental unit of chromatinthe nucleosome These chromatin elements are unstableand they change rapidly in response to any external stim-uli and any permanent changes to DNA can lead to the

development of defective organs or the development of adisease [1] Very sparse studies tend to show that histonemodifications are linked with CVD In normal mice fedwith propylthiouracil (PTU an inhibitor of T3 production)Pandya et al have shown that the distribution of histone3 lysine 4 trimethylation at a myosin-heavy chain relatedlocus was reversibly altered in ventricles suggesting thathistone 3 lysine 4 trimethylationmodification is an epigeneticmarker associated with changes in myosin-heavy chain generegulation [27] Histone acetylation is a dynamic processregulated by histone acetyltransferases and histone deacety-lases (HDACs) The balance between these two enzymefamilies is crucial to regulating gene expression and could beincriminated in CVD development [28] In rats inhibiting aspecific type of HDAC in the heart promotes cardiac stemcell-promoted cardiac regeneration which in turn inducesa partial restoration of cardiac function [29] These animalstudies give hope that histonemodification is a promisingwayto develop innovative biomarkers and therapies in the CVDfield

To date there are however very few significant reportsin human related to posttranslational histone modificationsin the area of CVD risk to be discussed Ek et al usinga genomewide DNA methylation study have shown thatgrowth-differentiation factor 15 is associated withmyocardialinfarction and that interestingly growth-differentiation fac-tor 15 mRNA was regulated by a specific small RNA miR-21leading us to the next chapter in our review [30]

5 RNA-Based Mechanisms

51 Noncoding RNAs in the Management of CardiovascularRisk Noncoding RNAs including microRNAs (miRNAs)and the recently discovered long noncodingRNAs (lncRNAs)are defined as a novel class of endogenous RNAs that regulatethe human genome and are not translated into proteinsThey have been shown to be implicated in cardiovascularphysiopathology A large number of long noncoding RNAsand microRNAs were in recent years implicated in cellularand animal models of cardiovascular diseases (CVD) andwere shown to be deregulated in patients with CVD We willdiscuss here their potential role as biomarkers in the CVDcontext Also as the miRNAs and lncRNAs we discuss mayrepresent novel targets to treat or prevent CVD we will seehow they could be used for the delivery of new treatments inCVD using groundbreaking techniques

52 miRNAs as Biomarkers in CVD It has been now 17 yearssince the existence of microRNAs (miRNAs) was shown inhuman These short endogenous interfering RNAs are codedby the human genome represent a new class of thousands ofRNAs of approximately 20 to 25 nucleotides (see specializedInternet databases such asmiRbase httpwwwmirbaseorgcgi-binmirna summaryplorg=hsa) and have emerged asregulators of numerous physiological and pathological pro-cesses [31] including CVDs [32 33] Their number is nowestimated to be around 2000 but a recent study using thor-oughRNApurification fromhuman cells and next generation

BioMed Research International 3

sequencing claims that there exist up to 5000 miRNAs withmore than a half being human specific [34]

53 miRNA Biogenesis In the canonical pathway a largeRNA precursor pri-miRNA is transcribed and matured inthe nucleus by the RNA polymerase II It is subsequentlycleaved near the hairpin stem base by RNase III Droshaand protein partner Di George syndrome critical region 8Thus the pre-miRNA precursor a hairpin of approx 60 to70 nucleotides is obtained which is then released in thecytoplasm It will be cleaved in its stems by the RNase IIIDicer This results in the double stranded miRNAmiRNAlowastduplex (21ndash25 base-pairs) which is unwound by RNA-induced-silencing complex (RISC) RISC will then carry themature miRNA to target messenger RNAs resulting in genesilencingMost of the time the bindingwill take place in the 31015840untranslated region andwill decrease targetmRNA levels andtranslation [35] Noncanonical pathways such as the mirtronpathway (in this instance miRNAs arise from introns) havealso been described [36]

54 MicroRNAs as Predictors of CVD Outcome As is abun-dantly explained in this special issue CVD are one ofmost common causes of premature death in the generalpopulation with an increasing number of individuals at riskNew biomarkers are needed to better stratify the risk ofprogression or the risk of specific complications associatedwith CVD and noncoding RNAs are prime candidates APubMed search using the terms cardiovascular + mirna +biomarker brings 969 results in May 2017 further highlight-ing the interest in the field

It was reasonable to hypothesize that miRNAs would bedifferentially expressed between the general population andpatients at risk of developing CVD or suffering from CVDFor instance we have shown that several miRNAs are differ-entially expressed in the carotid plaque between symptomaticpatients (having developed a stroke of ischemic transientepisode) and asymptomatic patients (having carotid plaquesremoved by surgery but without pathological episode) [37]Often however the clinician does not have access to thepathological tissue In a groundbreaking work Mitchell et al[38] have demonstrated that circulating miRNAs are presentin the human blood where they are carried in complexwith the chaperon argonaute 2 andor lipoproteins or bymicrovesicles conferring stability and protection againstRNases [39] Correlations exist between blood miRNA levelsand pathologies indicating that miRNAs are potential non-invasive biomarkers [40] It is thus reasonable to hypothesizethat miRNA seric or plasma expression is a most promisingavenue to evaluate early risk and patient outcome but alsoindividual patient response to various treatments or surgicalprocedures At first miRNAs were considered tissue and cellspecific and it was thus expected that their serum expressionwould reflect pathophysiology of concerned organs This isnow controversial and most miRNAs are rather enrichedfor a peculiar tissue miRNAs are usually quantified usingreverse transcription-quantitative PCR so the appropriateinternal control gene is very important for obtaining accurateresults of miRNA expression However there still has been

controversy about the choice of gene used as an internalcontrol [41] Currently the most widely used and acceptedinternal controls for miRNA qPCR are spiked-in exogenousnonhuman miRNA (eg synthetic Caenorhabditis elegansmiR-39) to avoid further experimental bias [41] Please notethat urinary miRNA also represents a potential novel sourceto discover noninvasive biomarkers for CVD [42]

We now know that cardiospecific miRNAs are highlystable in the blood [37] The pioneering work of Dimmeleret al highlighted a change in miRNA levels in the serumof patients with coronary artery disease (CAD) compared tocontrols [43] and miRNAs are now potential biomarkers forCVD [32] Since this pioneering study others have shownthat miRNAs are biomarkers able to predict CVD outcomeFor example Seronde et al have shown in a cohort of340 patients that decreased seric levels of miR-423-5p wereassociated with a poor long-term outcome in acute heartfailure patients [8] indicating the value of this miRNA asa prognostic biomarker of acute heart failure The largestcohort published to date (1114 patients) indicates that sericlevels of miR-132 miR-140-3p and miR-210 were able toprecisely predict cardiovascular death (the main outcome) inpatients suffering from acute coronary syndrome diagnosis[9]

miRNAs are interesting biomarkers to predict CVDoutcome in populations that are particularly at risk Thisis for instance true in the chronic kidney disease (CKD)population that is especially at risk for CVD [10 11] Ourexperimental data [12 13] suggests that miR-126 miR-143miR-145 miR-155 and miR-223 are potential circulatingbiomarkers for the diagnosis and prognosis of patients withCKD to assess the levels of miRNA expression at variousstages of CKD such as vascular calcifications [13] justifyingfurther studies to correlate alterations of miRNA levels withCVD outcome in CKD patients Also the levels of several ofthese miRNAs are sensitive to circulatory stresses and couldprovide valuable data about the way patients regulate theirblood pressure [14]

Gupta et al have shown that miR-22 regulates cardiacautophagy especially in the myocardium of senior patientsand that the circulating levels of miR-22 give prognosticinformation on eventual progression towards heart failuregiving interesting clues about miR-22rsquos role as biomarkercandidate for CVD in the elderly population [15] miRNAshave also potential to predict the cardiovascular toxicity ofdrugs and could for example help to detect anthracycline-induced cardiac damage Piegari et al have shown that miR-34 can predict the cardiotoxic effects of the anticancer drugdoxorubicin at least in a murine model [16]

As miRNAs are potential biomarkers in type 2 diabetesmellitus obesity and cardiovascular diseases they have alsobeen proposed tomonitor the physiological effects of exercisein the general population [44] For example miR-146a andmiR-221 levels were decreased and miR-149lowast was increasedafter acute exercise [17] whereas endurance exercise alteredthe expression of miR-1 miR-133 and miR-206 [19] Thesame was also true for patients at risk such as a populationof chronic kidney disease patients where acute exerciseincreased miR-150 levels and decreased miR-146a levels [18]


Table 1 miRNAs implicated in CVD

Pathophysiology RefmiR-423 Acute heart failure [8]miR-132 -140 -210 Cardiovascular death [9]miR-126 miR-143miR-145 miR-155miR-223

Vascular calcifications linked tochronic kidney disorders [10ndash14]

miR-22 Cardiac autophagy [15]miR-34 Cardiotoxic effect of doxorubicin [16]miR-146a -150miR-221 miR-149lowast Acute exercise [17 18]

miR-1 -133 -206 Endurance exercise [19]miR-1 Strength training [20]

miR-1 was also described as a potential biomarker in anelderly population submitted to eccentric and conventionalstrength training [20]

Table 1 resumes the main miRNAs implicated in CVD

55 Long Noncoding RNAs (lncRNAs) We now know thatmiRNAs are regulated at least in part by lncRNAs longtranscripts (gt200 nt) that do not code for proteins Thebiogenesis and molecular mechanism of action of miRNAsand lncRNAs have been described in greater detail in otherreviews [26 33 44 45] According to recent databases 56018and 46475 lncRNA genes have been respectively foundfor human and mouse lncRNAs differ from miRNAs asthey regulate gene expression not only at the transcrip-tional and but also at the posttranscriptional and chromatinremodeling levels They also have high tissular specificityand are not evolutionarily conserved lncRNA can act asdecoy for microRNA to allow microRNAsrsquo target mRNAto escape from degradation (reviewed by [44]) The use oflncRNAs as innovative biomarkers in the field is still in itsinfancy compared to themiRNA field Some really promisingcandidates such as LIPCAR [46] or UCA1 [47] have beenpublished in the CVD field and more are yet to come

56 Gene Therapy via MicroRNAs Can It Work in theCVD Field As miRNAs are promising biomarkers they arealso logical candidates to design innovative gene therapiesespecially as several genes are involved inmost cardiovasculardisorders [48] And miRNAs are master gene regulators ableto regulate up to 100 mRNA targets often implicated in con-vergent pathways [33] We will however have to keep in mindseveral potential problems such as loss of the therapeuticRNAs due to nucleases andor uptake by macrophages andinefficient endocytosis by target cells

Several successes have been accomplished in humanpatients using antisense based miRNA inhibitors such asmiravirsen with minimal side effects [49] On the otherside we can also use overexpression of miRNAs dependingon the tissue and clinical context Chad Mirkinrsquos team hasdeveloped nanotechnologies based on gold nanoparticles thatcan be covalently linked with mature miRNA duplexes orantisense sequences Interestingly in rodents they can cross

the blood-brainblood-tumor barriers when administeredintravenously [50 51] miRNA-based therapies are at presentmostly developed in the cancer field but the CVD field willfollow without doubt with exciting times ahead of us

6 Conclusion

Epigenetics is a relatively new science that has a tremendouspotential to introduce new biomarkers in the CVD fieldand also new avenues for innovative therapies There areseveral potential benefits of the use of innovative epigeneticbiomarkers such as DNA methylation of specific genes (ieTRAF3 or PPM1A methylation patterns as explained in thisreview) or miRNAs (ie miR-132 miR-140-3p and miR-210as predictors of cardiovascular death) Compared to classicbiochemical biomarkers they can provide valuable dataabout gene functions and phenotypes that would be helpfulconcerning CVD diagnosis outcome prognosis treatmentmonitoring and stratification However one has to keep inmind that as with other scientific fields in their infancy asignificant number of clinical studies with large cohorts willnow have to be implemented to confirm that interest Alsobiologists will have to harmonize the methods of detection inorder to avoid biases linked to technical issues

Conflicts of Interest

The authors declare that there are no conflicts of interestregarding the publication of this paper

References

[1] C Abi Khalil ldquoThe emerging role of epigenetics in cardiovascu-lar diseaserdquoTherapeutic Advances in Chronic Disease vol 5 no4 pp 178ndash187 2014

[2] A L Webster M S Yan and P A Marsden ldquoEpigenetics andcardiovascular diseaserdquoCanadian Journal of Cardiology vol 29no 1 pp 46ndash57 2013

[3] T Muka F Koromani E Portilla et al ldquoThe role of epigeneticmodifications in cardiovascular disease A systematic reviewrdquoInternational Journal of Cardiology vol 212 pp 174ndash183 2016

[4] Z Hai and W Zuo ldquoAberrant DNA methylation in the patho-genesis of atherosclerosisrdquo Clinica Chimica Acta vol 456 pp69ndash74 2016

[5] B J Toghill A Saratzis S C Harrison A R VerissimoE B Mallon and M J Bown ldquoThe potential role of DNAmethylation in the pathogenesis of abdominal aortic aneurysmrdquoAtherosclerosis vol 241 no 1 pp 121ndash129 2015

[6] A Fernandez-Sanles S Sayols-Baixeras I Subirana I RDegano and R Elosua ldquoAssociation betweenDNAmethylationand coronary heart disease or other atherosclerotic events asystematic reviewrdquo Atherosclerosis 2017

[7] S Raghuraman I Donkin S Versteyhe R Barres and DSimar ldquoThe emerging role of epigenetics in inflammation andimmunometabolismrdquo Trends in Endocrinology amp Metabolismvol 27 no 11 pp 782ndash795 2016

[8] M-F Seronde M Vausort E Gayat et al ldquoCirculating microR-NAs and outcome in patients with acute heart failurerdquo PLoSONE vol 10 no 11 Article ID e0142237 2015


[9] M Karakas C Schulte S Appelbaum et al ldquoCirculating mic-roRNAs strongly predict cardiovascular death in patients withcoronary artery diseasemdashresults from the large AtheroGenestudyrdquo European Heart Journal vol 38 no 7 pp 516ndash523 2017

[10] K Simpson AWonnacott D J Fraser and T Bowen ldquoMicroR-NAs in diabetic nephropathy from biomarkers to therapyrdquoCurrent Diabetes Reports vol 16 no 3 article 35 2016

[11] V Metzinger-Le Meuth S Burtey P Maitrias Z A Massyand L Metzinger ldquoMicroRNAs in the pathophysiology ofCKD-MBD biomarkers and innovative drugsrdquo Biochimica etBiophysica Acta vol 1863 no 1 pp 337ndash345 2017

[12] E MrsquoBaya-Moutoula L Louvet V Metzinger-Le Meuth ZA Massy and L Metzinger ldquoHigh inorganic phosphate con-centration inhibits osteoclastogenesis by modulating miR-223rdquoBiochimica et Biophysica Acta vol 1852 no 10 pp 2202ndash22122015

[13] F Taıbi V Metzinger-Le Meuth E MrsquoBaya-Moutoula et alldquoPossible involvement of microRNAs in vascular damage inexperimental chronic kidney diseaserdquo Biochimica et BiophysicaActamdashMolecular Basis of Disease vol 1842 no 1 pp 88ndash982014

[14] AMondadori dos Santos LMetzinger O Haddad et al ldquoMiR-126 is involved in vascular remodeling under laminar shearstressrdquo BioMed Research International vol 2015 Article ID497280 11 pages 2015

[15] S K Gupta A Foinquinos S Thum et al ldquoPreclinical devel-opment of a microRNA-based therapy for elderly patientswith myocardial infarctionrdquo Journal of the American College ofCardiology vol 68 no 14 pp 1557ndash1571 2016

[16] E Piegari R Russo D Cappetta et al ldquoMicroRNA-34a reg-ulates doxorubicin-induced cardiotoxicity in ratrdquo Oncotargetvol 7 no 38 pp 62312ndash62326 2016

[17] S Sawada M Kon S Wada T Ushida K Suzuki and TAkimoto ldquoProfiling of circulating microRNAs after a bout ofacute resistance exercise in humansrdquo PLoS ONE vol 8 no 7Article ID e70823 2013

[18] A H Van Craenenbroeck K J Ledeganck K Van Ackerenet al ldquoPlasma levels of microRNA in chronic kidney diseasePatterns in acute and chronic exerciserdquo American Journal ofPhysiologymdashHeart and Circulatory Physiology vol 309 no 12pp H2008ndashH2016 2015

[19] S Nielsen C Scheele C Yfanti et al ldquoMuscle specific microR-NAs are regulated by endurance exercise in human skeletalmusclerdquo Journal of Physiology vol 588 part 20 pp 4029ndash40372010

[20] M Mueller F A Breil G Lurman et al ldquoDifferent molecularand structural adaptations with eccentric and conventionalstrength training in elderly men and womenrdquo Gerontology vol57 no 6 pp 528ndash538 2011

[21] O El-Maarri M Walier F Behne et al ldquoMethylation at globalLINE-1 repeats in humanblood are affected by gender but not byage or natural hormone cyclesrdquo PLoS ONE vol 6 no 1 ArticleID e16252 2011

[22] L Wei S Liu Z Su R Cheng X Bai and X Li ldquoLINE-1 hypomethylation is associated with the risk of coronaryheart disease in Chinese populationrdquo Arquivos Brasileiros deCardiologia vol 102 no 5 pp 481ndash487 2014

[23] R-T Lin E Hsi H-F Lin Y-C Liao Y-S Wang and S-H HJuo ldquoLINE-1 methylation is associated with an increased risk ofischemic stroke in menrdquo Current Neurovascular Research vol11 no 1 pp 4ndash9 2014

[24] M Rask-Andersen D Martinsson M Ahsan et al ldquoEpig-enome-wide association study reveals differential DNA methy-lation in individuals with a history of myocardial infarctionrdquoHuman Molecular Genetics vol 25 pp 4739ndash4748 2016

[25] C Gallego-Fabrega C Carrera J-L Reny et al ldquoPPM1Amethylation is associated with vascular recurrence in aspirin-treated patientsrdquo Stroke vol 47 no 7 pp 1926ndash1929 2016

[26] C Gallego-Fabrega C Carrera J L Reny et al ldquoTRAF3epigenetic regulation is associated with vascular recurrence inpatients with ischemic strokerdquo Stroke vol 47 no 5 pp 1180ndash1186 2016

[27] K Pandya T Kohro I Mimura et al ldquoDistribution of histone3lysine 4 trimethylation at T3-responsive loci in the heart duringreversible changes in gene expressionrdquo Gene Expression vol 15no 4 pp 183ndash198 2012

[28] J YangW Xu and S Hu ldquoHeart failure advanced developmentin genetics and epigeneticsrdquo BioMed Research International vol2015 Article ID 352734 11 pages 2015

[29] L X Zhang M DeNicola X Qin et al ldquoSpecific inhibitionof HDAC4 in cardiac progenitor cells enhances myocardialrepairsrdquo American Journal of PhysiologymdashCell Physiology vol307 no 4 pp C358ndashC372 2014

[30] W E Ek A K Hedman S Enroth et al ldquoGenome-wideDNA methylation study identifies genes associated with thecardiovascular biomarker GDF-15rdquoHumanMolecular Geneticsvol 25 no 4 pp 817ndash827 2016

[31] D P Bartel ldquoMicroRNAs target recognition and regulatoryfunctionsrdquo Cell vol 136 no 2 pp 215ndash233 2009

[32] S de Franciscis L Metzinger and R Serra ldquoThe discoveryof novel genomic transcriptomic and proteomic biomarkersin cardiovascular and peripheral vascular disease the state ofthe artrdquo BioMed Research International vol 2016 Article ID7829174 10 pages 2016

[33] F Taıbi V Metzinger-Le Meuth Z A Massy and L MetzingerldquoMiR-223 an inflammatory oncomiR enters the cardiovascularfieldrdquo Biochimica et Biophysica Acta vol 1842 no 7 pp 1001ndash1009 2014

[34] E Londin P Loher A G Telonis et al ldquoAnalysis of 13 cell typesreveals evidence for the expression of numerous novel primate-and tissue-specific microRNAsrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 112 no10 pp E1106ndashE1115 2015

[35] H Guo N T Ingolia J S Weissman and D P Bartel ldquoMam-malian microRNAs predominantly act to decrease targetmRNA levelsrdquo Nature vol 466 no 7308 pp 835ndash840 2010

[36] H J Curtis C R Sibley and M J A Wood ldquoMirtronsan emerging class of atypical miRNArdquo Wiley InterdisciplinaryReviews RNA vol 3 no 5 pp 617ndash632 2012

[37] P Maitrias V Metzinger-Le Meuth Z A Massy et alldquoMicroRNA deregulation in symptomatic carotid plaquerdquo Jour-nal of Vascular Surgery vol 62 no 5 pp 1245ndash1250e1 2015

[38] P S Mitchell R K Parkin E M Kroh et al ldquoCirculatingmicroRNAs as stable blood-based markers for cancer detec-tionrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 105 no 30 pp 10513ndash10518 2008

[39] M PHunterN Ismail X Zhang et al ldquoDetection ofmicroRNAexpression in human peripheral blood microvesiclesrdquo PLoSONE vol 3 no 11 Article ID e3694 2008

[40] P Menendez P Villarejo D Padilla J M Menendez and J AR Montes ldquoDiagnostic and prognostic significance of serummicroRNAs in colorectal cancerrdquo Journal of Surgical Oncologyvol 107 no 2 pp 217ndash220 2013


[41] T C Roberts A M L Coenen-Stass and M J A WoodldquoAssessment of RT-qPCR normalization strategies for accuratequantification of extracellular microRNAs in murine SerumrdquoPLoS ONE vol 9 no 2 Article ID e89237 2014

[42] H Schwarzenbach N Nishida G A Calin and K PantelldquoClinical relevance of circulating cell-free microRNAs in can-cerrdquoNature Reviews Clinical Oncology vol 11 no 3 pp 145ndash1562014

[43] S Fichtlscherer A M Zeiher and S Dimmeler ldquoCirculatingmicroRNAs biomarkers or mediators of cardiovascular dis-easesrdquo Arteriosclerosis Thrombosis and Vascular Biology vol31 no 11 pp 2383ndash2390 2011

[44] LNMasi TDA Serdan A C Levada-Pires et al ldquoRegulationof gene expression by exercise-related micrornasrdquo CellularPhysiology and Biochemistry vol 39 no 6 pp 2381ndash2397 2016

[45] S Uchida and S Dimmeler ldquoLong noncoding RNAs in cardio-vascular diseasesrdquo Circulation Research vol 116 no 4 pp 737ndash750 2015

[46] R Kumarswamy C Bauters I Volkmann et al ldquoCirculatinglong noncoding RNA LIPCAR predicts survival in patientswith heart failurerdquo Circulation Research vol 114 no 10 pp1569ndash1575 2014

[47] Y Yan B ZhangN Liu et al ldquoCirculating long noncodingRNAUCA1 as a novel biomarker of acute myocardial infarctionrdquoBioMed Research International vol 2016 Article ID 8079372 7pages 2016

[48] R F J Kwekkeboom Z Lei P A Doevendans R J P Mustersand J P G Sluijter ldquoTargeted delivery of miRNA therapeuticsfor cardiovascular diseases Opportunities and challengesrdquoClinical Science vol 127 no 6 pp 351ndash365 2014

[49] H L A Janssen H W Reesink E J Lawitz et al ldquoTreatmentof HCV infection by targeting microRNArdquo The New EnglandJournal of Medicine vol 368 no 18 pp 1685ndash1694 2013

[50] L Hao P C Patel A H Alhasan D A Giljohann and C AMirkin ldquoNucleic acid-gold nanoparticle conjugates as mimicsof microRNArdquo Small vol 7 no 22 pp 3158ndash3162 2011

[51] F M Kouri L A Hurley W L Daniel et al ldquoMiR-182integrates apoptosis growth and differentiation programs inglioblastomardquo Genes and Development vol 29 no 7 pp 732ndash745 2015

Submit your manuscripts athttpswwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


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Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

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OphthalmologyJournal of


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Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


and RNA-based mechanisms PubMed Scopus and Sci-ence Direct databases were used for the search strategy APubMed search using the terms cardiovascular + epigenetic+ biomarker found 261 results in May 2017

3 DNA Methylation

DNA methylation partly controlled by DNA methyltrans-ferases is usually associated with transcriptional repressionwhile demethylation is associated with transcriptional activa-tion influencing gene expression by altering DNA promoteraccessibility to RNA polymerase and consequently genetranscription [7] A PubMed search using the terms cardio-vascular + methylation + biomarker + biomarker found 185results in May 2017

In this context the concept of globalmethylation refers tothe overall level of methylcytosines in the genome expressedas percentage of total cytosines In fact a large proportionof methylation sites within the genome are found in repeatsequences and transposable elements such as Alu and long-interspersed nuclear element (LINE-1) and this correlateswith the total genomic methylation content and for thisreason LINE-1 is used as a surrogate for the overall methy-lation of the genome [3] Interestingly LINE-1 methylation isincreased in males [21] while it is not affected by either ageor natural cycle of hormones

Several research teams have studied the possibility thatDNA methylation could be correlated with the risk of CVDSeveral evidences showed that global DNA methylationassessed at LINE-1 sequences was inversely and indepen-dently related to CVD risk thus more proportions of globalDNA methylation are indicative of a higher CVD risk [3 2223] Very recently a Swedish team performed an epigenome-wide association study to identify disease-specific alterationsin DNA methylation in blood samples of a Swedish popula-tion of 729 patients afflicted with hypertension myocardialinfarction stroke thrombosis and cardiac arrhythmia [24]

For this they used an Illumina Infinium BeadChipDifferential DNAmethylation was detected inmore than 200CpG-sites in patients with a history of myocardial infarctionAmong these sites 42 genes were related to cardiac functionThe authors concluded that individuals with a history of MIhave an altered pattern of DNA methylation at numerousgenomic loci linked to CVD These sites are thus potentialbiomarkers for CVD [24] DNAmethylation in specific genescan also be helpful to predict response to a specific treatmentTwo elegant studies by Gallego-Fabrega et al have shownthat changes in DNA methylation patterns of PPM1A andTRAF3 are respectively associated with vascular recurrencein aspirin-treated patients and clopidogrel response andrecurrence of ischemic events in patients with stroke [25 26]

4 Posttranslational Histone Modifications

Eukaryotic DNA is wrapped around an octamer of thecore histones that build the fundamental unit of chromatinthe nucleosome These chromatin elements are unstableand they change rapidly in response to any external stim-uli and any permanent changes to DNA can lead to the

development of defective organs or the development of adisease [1] Very sparse studies tend to show that histonemodifications are linked with CVD In normal mice fedwith propylthiouracil (PTU an inhibitor of T3 production)Pandya et al have shown that the distribution of histone3 lysine 4 trimethylation at a myosin-heavy chain relatedlocus was reversibly altered in ventricles suggesting thathistone 3 lysine 4 trimethylationmodification is an epigeneticmarker associated with changes in myosin-heavy chain generegulation [27] Histone acetylation is a dynamic processregulated by histone acetyltransferases and histone deacety-lases (HDACs) The balance between these two enzymefamilies is crucial to regulating gene expression and could beincriminated in CVD development [28] In rats inhibiting aspecific type of HDAC in the heart promotes cardiac stemcell-promoted cardiac regeneration which in turn inducesa partial restoration of cardiac function [29] These animalstudies give hope that histonemodification is a promisingwayto develop innovative biomarkers and therapies in the CVDfield

To date there are however very few significant reportsin human related to posttranslational histone modificationsin the area of CVD risk to be discussed Ek et al usinga genomewide DNA methylation study have shown thatgrowth-differentiation factor 15 is associated withmyocardialinfarction and that interestingly growth-differentiation fac-tor 15 mRNA was regulated by a specific small RNA miR-21leading us to the next chapter in our review [30]

5 RNA-Based Mechanisms

51 Noncoding RNAs in the Management of CardiovascularRisk Noncoding RNAs including microRNAs (miRNAs)and the recently discovered long noncodingRNAs (lncRNAs)are defined as a novel class of endogenous RNAs that regulatethe human genome and are not translated into proteinsThey have been shown to be implicated in cardiovascularphysiopathology A large number of long noncoding RNAsand microRNAs were in recent years implicated in cellularand animal models of cardiovascular diseases (CVD) andwere shown to be deregulated in patients with CVD We willdiscuss here their potential role as biomarkers in the CVDcontext Also as the miRNAs and lncRNAs we discuss mayrepresent novel targets to treat or prevent CVD we will seehow they could be used for the delivery of new treatments inCVD using groundbreaking techniques

52 miRNAs as Biomarkers in CVD It has been now 17 yearssince the existence of microRNAs (miRNAs) was shown inhuman These short endogenous interfering RNAs are codedby the human genome represent a new class of thousands ofRNAs of approximately 20 to 25 nucleotides (see specializedInternet databases such asmiRbase httpwwwmirbaseorgcgi-binmirna summaryplorg=hsa) and have emerged asregulators of numerous physiological and pathological pro-cesses [31] including CVDs [32 33] Their number is nowestimated to be around 2000 but a recent study using thor-oughRNApurification fromhuman cells and next generation























6 Conclusion




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the management of cardiovascular risk through epigenetic … · 2019. 5. 12. · 4...

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