Mediators of Inflammation Atherosclerosis in Rheumatoid Arthritis Guest Editors: Miguel A. González-Gay, Zoltan Szekanecz, Calin D. Popa, and Patrick Dessein Atherosclerosis in Rheumatoid Arthritis Mediators of Inflammation Atherosclerosis in Rheumatoid Arthritis Guest Editors: Miguel A. Gonza´lez-Gay, Zoltan Szekanecz, Calin D. Popa, and Patrick Dessein Copyright©2012HindawiPublishingCorporation.Allrightsreserved. Thisisaspecialissuepublishedin“MediatorsofInflammation.”AllarticlesareopenaccessarticlesdistributedundertheCreativeCom- monsAttributionLicense,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalwork isproperlycited. Editorial Board AnshuAgrawal,USA NinaIvanovska,Bulgaria VeraL.Petricevich,Mexico MuzamilAhmad,India YongJiang,China PeterPlomgaard,Denmark SimiAli,UK YonaKeisari,Israel MarcPouliot,Canada PhilipBufler,Germany AlexKleinjan,TheNetherlands MichalAmitRahat,Israel HiddeBult,Belgium MagdalenaKlink,Poland Jean-MarieReimund,France ElisabettaBuommino,Italy ElzbietaKolaczkowska,Poland AlexanderRiad,Germany DianneCooper,UK DmitriV.Krysko,Belgium HuubSavelkoul,TheNetherlands GuanglinCui,Norway JoanKwakkel,TheNetherlands NatalieJ.Serkova,USA FulvioD’Acquisto,UK PhilippM.Lepper,Germany SunitKumarSingh,India PhamMy-ChanDang,France ChanglinLi,USA DirkE.Smith,USA BeatrizDelasHeras,Spain EduardoLo´pez-Collazo,Spain HelenC.Steel,SouthAfrica ChiaraDeLuca,Italy AntonioMaccio`,Italy DennisDanielTaub,USA YvesDenizot,France A.Malamitsi-Puchner,Greece KathyTriantafilou,UK ClaraDiFilippo,Italy SunilKumarManna,India FumioTsuji,Japan BrunoL.Diaz,Brazil FrancescoMarotta,Italy PeterUciechowski,Germany MaziarDivangahi,Canada Donna-MarieMcCafferty,Canada GiuseppeValacchi,Italy AmosDouvdevani,Israel Ce´lineMe´hats,France LucVallie`res,Canada GiamilaFantuzzi,USA BarbroMelgert,TheNetherlands JanvanAmsterdam,TheNetherlands StefanieB.Flohe´,Germany VinodK.Mishra,USA ElenaVoronov,Israel TaˆniaSilviaFro¨de,Brazil E.Moilanen,Finland JyotiJ.Watters,USA JulioGalvez,Spain EricF.Morand,Australia SohYamazaki,Japan ChristophGarlichs,Germany JonasMudter,Germany SatoruYui,Japan RonaldGladue,USA MarjaOjaniemi,Finland TeresaZelante,Singapore HermannGram,Switzerland SandraH.P.Oliveira,Brazil DezhengZhao,USA OresteGualillo,Spain AndrewParker,Switzerland FreekJ.Zijlstra,TheNetherlands ElaineHatanaka,Brazil JonathanPeake,Austria Contents AtherosclerosisinRheumatoidArthritis,MiguelA.Gonza´lez-Gay,ZoltanSzekanecz,CalinD.Popa, andPatrickDessein Volume2012,ArticleID489608,2pages AtherosclerosisandRheumatoidArthritis:MoreThanaSimpleAssociation,LorenzoCavagna, NicolaBoffini,GiovanniCagnotto,FloraInverardi,VittorioGrosso,andRobertoCaporali Volume2012,ArticleID147354,8pages AtherogenicIndexandHigh-DensityLipoproteinCholesterolasCardiovascularRiskDeterminantsin RheumatoidArthritis:TheImpactofTherapywithBiologicals,CalinD.Popa,ElkeArts,JaapFransen, andPietL.C.M.vanRiel Volume2012,ArticleID785946,9pages AtherosclerosisinJuvenileIdiopathicArthritis,EwaJednaczandLidiaRutkowska-Sak Volume2012,ArticleID714732,5pages SerumLevelsofAsymmetricDimethylarginineandApelinasPotentialMarkersofVascularEndothelial DysfunctioninEarlyRheumatoidArthritis,ManuelaDiFranco,FrancescaRomanaSpinelli, AlessioMetere,MariaChiaraGerardi,VirginiaConti,FrancescaBoccalini,CristinaIannuccelli, FrancescoCiciarello,LucianoAgati,andGuidoValesini Volume2012,ArticleID347268,7pages GeneticMarkersofCardiovascularDiseaseinRheumatoidArthritis,LuisRodr´ıguez-Rodr´ıguez, RaquelLo´pez-Mej´ıas,MercedesGarc´ıa-Bermu´dez,CarlosGonza´lez-Juanatey,MiguelA.Gonza´lez-Gay, andJavierMart´ın Volume2012,ArticleID574817,14pages Anti-TNF-Alpha-AdalimumabTherapyIsAssociatedwithPersistentImprovementofEndothelial FunctionwithoutProgressionofCarotidIntima-MediaWallThicknessinPatientswithRheumatoid ArthritisRefractorytoConventionalTherapy,CarlosGonzalez-Juanatey,TomasR.Vazquez-Rodriguez, JoseA.Miranda-Filloy,InesGomez-Acebo,AnaTesta,CarlosGarcia-Porrua,AmaliaSanchez-Andrade, JavierLlorca,andMiguelA.Gonza´lez-Gay Volume2012,ArticleID674265,8pages RoleofAdipokinesinAtherosclerosis:InterferenceswithCardiovascularComplicationsinRheumatic Diseases,MorenaScotece,JavierConde,RodolfoGo´mez,Vero’nicaLo´pez,Jesu´sPino,AntonioGonza´lez, FranciscaLago,JuanJ.Go´mez-Reino,andOresteGualillo Volume2012,ArticleID125458,14pages HindawiPublishingCorporation MediatorsofInflammation Volume2012,ArticleID489608,2pages doi:10.1155/2012/489608 Editorial Atherosclerosis in Rheumatoid Arthritis MiguelA.Gonza´lez-Gay,1ZoltanSzekanecz,2CalinD.Popa,3andPatrickDessein4 1DivisionofRheumatology,HospitalUniversitarioMarqu´esdeValdecilla,IFIMAV,39008Santander,Spain 2DepartmentofRheumatology,InstituteofMedicine,UniversityofDebrecenMedicalandHealthSciencesCenter, 98NagyerdeiStreet,DebrecenH-4032,Hungary 3DepartmentofRheumatology,RadboudUniversityNijmegenMedicalCentre,P.O.Box9101,6500HBNijmegen,TheNetherlands 4ResearchUnitofCardiovascularPathophysiologyandGenomics,SchoolofPhysiology,FacultyofHealthSciences, UniversityoftheWitwatersrandandCharlotteMaxekeJohannesburgAcademicHospital,Johannesburg2193,SouthAfrica CorrespondenceshouldbeaddressedtoMiguelA.Gonza´lez-Gay,[email protected] Received30September2012;Accepted30September2012 Copyright©2012Miguel A. Gonza´lez-Gay et al. This is an open access article distributed under the Creative Commons AttributionLicense,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkis properlycited. Thereisagrowingbodyofevidencesupportinganincreased of different autoimmune diseases [9, 10]. A timely review risk of cardiovascular (CV) mortality in patients with ontheimplicationofadipokinesinthedevelopmentofthe rheumatoid arthritis (RA). This is the result of complex atherosclerotic disease not only focusing on RA but also mechanisms leading to accelerated atherosclerosis [1]. In discussingthelinkbetweenthesemoleculesandthepresence this regard, besides classic CV risk factors [2], chronic of atherosclerosis in other chronic inflammatory rheumatic inflammation[3]andageneticcomponent[3,4]havebeen diseaseswasincludedinthespecialissue. proposedtoinfluencethedevelopmentofatherosclerosisin The mechanisms associated with endothelial dysfunc- RA. tion, an early step in the atherogenesis process, in patients This special issue encompasses different aspects of the with RA are far from being completely understood. In CV disease associated to RA. With respect to this, the link this special issue an assessment of the potential role of between atherosclerosis and RA was discussed. Surrogate asymmetric dimethylarginine and apelin as biomarkers to markers of atherosclerosis have been found to be useful detectearlydataofendothelialdysfunctioninpatientswith in predicting the presence of atherosclerosis disease in RAwasincluded. subclinical stages in adults with RA [5, 6]. Data shown in Anti-TNF-αdrugsconstitutethemainstayoftherapyin this special issue also confirmed that children with juvenile RApatientswithseverediseasethatisrefractorytoconven- idiopathic arthritis may have higher carotid intima-media tional disease modifying antirheumatic drugs. One of the wallthicknessindexvaluesthancontrols.Theseobservations articlesincludedinthespecialissueconfirmedthepreviously emphasize the need for increased awareness of the risk of reportedshort-termbeneficialeffectofthefullyhuman-anti- atherosclerosisinchildrenwithjuvenileidiopathicarthritis. TNF-α monoclonal antibody adalimumab on endothelial An exhaustive literature review on the genetic influence function [11]. In addition, new data showing persistent in the development of CV disease in patients with RA was improvementofendothelialfunctioninadalimumab-treated also included. With respect to this, it is important to keep RApatientswithoutprogressionofthecarotidintima-media inmindthatbesidesgenepolymorphismslocatedwithinthe thickness are reported. This is of potential relevance as MHC region [3, 4], variations of genes located outside this the use of anti-TNF-α therapy has been associated with region,suchasCCR5,MTHF[7,8],areofpotentialrelevance a decrease of mortality in RA patients, mainly due to a intheincreasedriskofCVdiseaseassociatedtoRA. reductionintheincidenceofCVevents[12]. Adipokines are molecules not only implicated in the In line with the above, Popa et al. had previously development of metabolic syndrome but also in inflamma- assessed the effects of the anti-TNF-α therapy on the HDL tory mechanisms that may play a role in the pathogenesis antiatherogenic function. They observed that infliximab, 2 MediatorsofInflammation achimericanti-TNF-αmonoclonalIgG1antibodywasable [11] C. Gonzalez-Juanatey, J. Llorca, A. Sanchez Andrade, C. to improve HDL antioxidative capacity. This effect was Garcia-Porrua, J. Martin, and M. A. Gonzalez-Gay, “Short- sustained 6 months after anti-TNF-α therapy had been term adalimumab therapy improves endothelial function in initiated[13].Inthisspecialissuethesamegroupconducted patients with rheumatoid arthritis refractory to infliximab,” an extensive review on the effect that different biologic Clinical and Experimental Rheumatology, vol. 24, no. 3, pp. 309–312,2006. therapiesexertontheatherogenicindexandHDLcholesterol [12] C.Barnabe,B.J.Martin,andW.A.Ghali,“Systematicreview inpatientswithRA. andmeta-analysis:anti-tumornecrosisfactorαtherapyand Taken together, these studies confirm the presence of cardiovasculareventsinrheumatoidarthritis,”ArthritisCare complex mechanisms that influence the development of andResearch,vol.63,no.4,pp.522–529,2011. atherosclerosis in RA. Nevertheless, further studies are [13] C.Popa,L.J.H.VanTits,P.Barreraetal.,“Anti-inflammatory needed to shed light on the problem of augmented risk of therapywithtumournecrosisfactoralphainhibitorsimproves CVdiseaseinpatientswithRA. high-density lipoprotein cholesterol antioxidative capacity in rheumatoid arthritis patients,” Annals of the Rheumatic MiguelA.Gonza´lez-Gay Diseases,vol.68,no.6,pp.868–872,2009. ZoltanSzekanecz CalinD.Popa PatrickDessein References [1] M. A. Gonzalez-Gay, C. Gonzalez-Juanatey, and J. Martin, “Rheumatoid arthritis: a disease associated with accelerated atherogenesis,”SeminarsinArthritisandRheumatism,vol.35, no.1,pp.8–17,2005. [2] P.H.Dessein,B.I.Joffe,M.G.Velleretal.,“Traditionaland nontraditionalcardiovascularriskfactorsareassociatedwith atherosclerosisinrheumatoidarthritis,”JournalofRheumatol- ogy,vol.32,no.3,pp.435–442,2005. [3] M.A.Gonzalez-Gay,C.Gonzalez-Juanatey,M.J.Lopez-Diaz etal.,“HLA-DRB1andpersistentchronicinflammationcon- tributetocardiovasculareventsandcardiovascularmortality in patients with rheumatoid arthritis,” Arthritis Care and Research,vol.57,no.1,pp.125–132,2007. [4] L.Rodr´ıguez-Rodr´ıguez,C.Gonza´lez-Juanatey,R.Palomino- Morales et al., “TNFA -308 (rs1800629) polymorphism is associated with a higher risk of cardiovascular disease in patients with rheumatoid arthritis,” Atherosclerosis, vol. 216, no.1,pp.125–130,2011. [5] M. A. Gonzalez-Gay, C. Gonzalez-Juanatey, T. R. Vazquez- Rodriguez,J.Martin,andJ.Llorca,“Endothelialdysfunction, carotid intima-media thickness, and accelerated atheroscle- rosis in rheumatoid arthritis,” Seminars in Arthritis and Rheumatism,vol.38,no.2,pp.67–70,2008. [6] G. Kerekes, P. Solte´sz, M. T. Nurmohamed et al., “Validated methods for assessment of subclinical atherosclerosis in rheumatology,”NatureReviewsRheumatology,vol.8,no.4,pp. 224–234,2012. [7] L. Rodr´ıguez-Rodr´ıguez, C. Gonza´lez-Juanatey, M. Garc´ıa- Bermu´dezetal.,“CCR5Δ32variantandcardiovasculardisease inpatientswithrheumatoidarthritis:acohortstudy,”Arthritis ResearchandTherapy,vol.13,no.4,articleR133,2011. [8] R. Palomino-Morales, C. Gonzalez-Juanatey, T. R. Vazquez- Rodriguezetal.,“A1298CpolymorphismintheMTHFRgene predisposes to cardiovascular risk in rheumatoid arthritis,” ArthritisResearchandTherapy,vol.12,no.2,article71,2010. [9] R.Go´mez,J.Conde,M.Scotece,J.J.Go´mez-Reino,F.Lago, and O. Gualillo, “What’s new in our understanding of the role of adipokines in rheumatic diseases?” Nature Reviews Rheumatology,vol.7,no.4,pp.528–536,2011. [10] M. A. Gonzalez-Gay, M. T. Garcia-Unzueta, C. Gonzalez- Juanatey et al., “Anti-TNF-α therapy modulates resistin in patientswithrheumatoidarthritis,”ClinicalandExperimental Rheumatology,vol.26,no.2,pp.311–316,2008. HindawiPublishingCorporation MediatorsofInflammation Volume2012,ArticleID147354,8pages doi:10.1155/2012/147354 Review Article Atherosclerosis and Rheumatoid Arthritis: More Than a Simple Association LorenzoCavagna,NicolaBoffini,GiovanniCagnotto,FloraInverardi, VittorioGrosso,andRobertoCaporali DepartmentofRheumatology,UniversityandIRCCSFoundationPoliclinicoSanMatteo,VialeGolgi19,27100Pavia,Italy CorrespondenceshouldbeaddressedtoLorenzoCavagna,[email protected] Received25June2012;Accepted10July2012 AcademicEditor:MiguelA.Gonza´lez-Gay Copyright©2012LorenzoCavagnaetal. This is an open access article distributed under the Creative Commons Attribution License,whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperly cited. Inthelastdecadesalargeamountofevidencelinkedrheumatoidarthritis(RA)toatherosclerosis.Infact,RApatientshavean increasedriskofcardiovasculareventsthatisnotfullyexplainedbyotherclassiccardiovascularriskfactors.RAandatherosclerosis may share several common pathomechanisms and inflammation undoubtedly plays a primary role. The proinflammatory cytokines such as tumor necrosis factor alpha and interleukin-6, involved in the pathogenesis of RA, are also independently predictiveofsubsequentcardiovasculardisease(CVD).InRA,inflammationaltersHDLconstituentsandtheconcentrationofLDL andHDL,thusfacilitatingatherosclerosisandCVDevents.Ontheotherhand,alsotheincreaseofoxidativeprocesses,frequently observed in RA, induces atherosclerosis. Interestingly, some genetic polymorphisms associated with RA occurrence enhance atherosclerosis, however, other polymorphisms associated with RA susceptibility do not increase CVD risk. Several other mechanismsmayinfluenceatheroscleroticprocessesinRA.Moreover,atherosclerosismaybedirectlymediatedalsobyunderlying autoimmuneprocesses,andindirectlybytheoccurrenceofmetabolicsyndromeandimpairedphysicalactivity.Finally,theeffects ofRAtherapiesoncardiovascularsystemingeneralandonatherosclerosisinparticulararereallywideanddifferent.However,the startingpointofeveryRAtreatmentisthatdiseasecontrol,orbetterremission,isthebestwaywehaveforthereductionofCVD occurrence. 1.Introduction 2.TheLinkbetweenAtherosclerosis andRheumatoidArthritis Rheumatoid arthritis (RA) and atherosclerosis are two inflammatorydiseasesstrictlylinked;infact,althoughjoint In the last years, a large amount of data improved the involvementistheprototypicalfeatureofRA,atherosclerotic understandingofpathomechanismsleadingtoatherosclero- cardiovascular diseases (CVDs) are the major cause of sisappearance,thusallowingitsclassificationamonginflam- mortality and morbidity in these patients [1, 2]. Therefore, matorydisorders[4],similarlytoRA.Butthisisnottheonly theincreasedCVDriskoccursevenearlyduringthecourseof pointthatlinksatherosclerosisandRA;undoubtedly,smoke RA,beingsointendedasapossiblepreclinicalmanifestation isthemostevidentone,beingclearlyinvolvedintheappear- ofthedisease[3].Onthisbasis,theunderstandingofcom- ance of both diseases [5, 6]. Moreover, it is well established monly shared pathomechanisms is mandatory for the right that RA patients had an increased risk of cardiovascular treatment of RA, in order to reduce atherosclerosis and the eventsthatisnotfullyexplainedbysmokeandotherclassic subsequentimpactofCVD,onthesepatients.Moreover,it’s CVDriskfactors[3].Therefore,atheroscleroticprocessesare also important to evaluate the different effects of RA increased in RA [7, 8], and subsequently also CVD risk. therapies(i.e.,corticosteroids,NSAIDs,DMARDs,anti-TNF Inflammation plays a primary role in this relationship; in agents,andotherbiologicaldrugs)oncardiovascularrisk.All fact,inpatientswithrecentonsetpolyarthritis,baselineCRP theseaspectswillbeanalyzedinthispaper. levels were independent predictors of CVD-related death, 2 MediatorsofInflammation withanhazardratioof3.3,andthisafteradjustingforage, But although these factors are important, the “sine qua sex, smoking status, rheumatoid factor positivity, swollen non” condition for atherosclerosis appearance is the occur- joint counts, and Health Assessment Questionnaire score rence of endothelial dysfunction, a feature frequently des- [9].Furthermore,itisinterestingtoobservethattheriskof cribed in RA patients [22]; this generic term indicates the CVDevents,myocardialinfarctioninparticular,isincreased endothelialphenotypicalterationsthatappearinresponseto also in the 2 years preceding formal diagnosis of RA [10]; alargeamountofnoxiousstimuli.Theincreasedexpression so, on this basis, it is possible to speculate that systemic of adhesion molecules such as ICAM-1, VCAM-1 and inflammation may increase atherosclerosis before it affects E-selectin,theenhancementofpro-inflammatorycytokines the joints [11]. On the other hand, the longer the duration (TNF-α,IL-1,IL-6,IFN-γ),andtheupregulationofoxidative ofdisease,thehighertheriskofplaquesinthecarotidartery stress processes are the starting point of this condition [12]andCVDevents[13],thusindicatingthatchronicRA- [23]; moreover, also the increase of leptin and resistin relatedinflammationincreasestheCVDriskandsuggesting (proatherogenichormones)andthedecreaseofadiponectin the need of early therapeutic intervention in these patients. (antiatherogenic hormones) may alter endothelial home- Therefore,betweentheproinflammatorycytokinesinvolved ostasisinRApatients[22].Thesefeaturesleadtoanincrease inthepathogenesisofRA,tumornecrosisfactor(TNF)alpha inendothelialpermeabilitytolipoproteinsandplasmacon- andinterleukin(IL)-6areindependentlypredictiveofsubse- stituents, with subsequent infiltration of lipids into the quentCVDeventsinthesepatients.Infact,thesecytokines arterialwallandmigrationofmonocytesandT-lymphocytes are released into the systemic circulation, with a large into the vessel intima [24]. Foam cells and fatty streaks amount of systemic effects, in particular on endothelium appearance within the vessel wall is the consequence of [11]. The result is a cascade of alterations throughout our theseprocesses[25].Theinflammatorystateleadstosmooth organism that leads to the proatherogenic profile that is musclecellsproliferation,thatmigratesintothelesionwith prototypicalofRA. subsequentvesselwallsthickeningandfibrotictissuedeposi- tion.Theresultistheappearanceofatheroscleroticplaques, that appear as a dynamic lesions, due to the large amount 3.PathomechanismsInvolvedinRheumatoid of ongoing modifying processes; but these lesions are also AtherosclerosisAppearance unstable, with an increased risk of rupture [24]. Therefore, recentdatashowedthatendothelialprogenitorcells(EPCs) RA-relatedinflammationmayleadtoatherosclerosisoccur- action is altered in RA [26]; EPCs are mononuclear cells renceinseveralways.Theenhancementofoxidativemodifi- presentinblood,bonemarrow,andvesselsthatexpressspe- cationofLDL,thathasbeenlinkedtoTNF-αactionthrough cific endothelial markers and can help the repair of injured the stimulation of superoxide secretion from monocytes endothelium[11].So,onthisbasisitispossibletospeculate and endothelial cells, is among involved processes [11]; that in RA not only atherosclerosis formation mechanisms moreover, also HDL constituents may be altered by the areincreased,butalsoreparatorymechanismsareimpaired. inflammation,thuslosingtheirabilitytoremovecholesterol from atherosclerotic lesions and reducing their antioxidant activity [14]. On the other hand, not only the function 4.GeneticandAutoimmunity:BesideClassic but also the concentration of LDL and HDL is altered in InflammationPathways RA; in particular small-dense LDLs are increased, whereas small-dense HDLs are decreased [11], thus leading to an After the identification through genome-wide association unbalance toward atherosclerosis appearance. Therefore, studiesofalargeamountofputativelocithatmayincrease HDL impairment may be related to paraoxonase (PON) theriskofCVDinthegeneralpopulation,severalresearches activity reduction, that has been found in RA, in particular have been addressed to the identification of a genetic back- inpatientswithbothactive[15]andquiescentdisease[16]; grounds also for RA-related atherosclerosis. In particular, infact,PONisapeculiarenzymelinkedtoHDLthatbinds recent data evidenced that rs599839 A/G polymorphism and destroys oxidized lipids, thus reducing atherosclerosis (chromosome 1p13.3), previously associated with higher occurrence [11]. Another aspect is the increase of oxidative plasmatotalandLDLcholesterollevelsandwithanincreased processes, that in RA is demonstrated in several ways, for risk of CVD in general population, seems to increase the example, by the depletion of vitamins A and E and by the risk of endothelial dysfunction also in RA patients without reduced degradation of asymmetric dimethyl-L-arginine evidence of overt CVD [27]. Another identified polymor- (ADMA), an endogenous inhibitor of nitric oxide synthase phism,MIA3rs17465637A/C,enhancestheriskofCVDalso (NOS)[11,17].Recently,theattentionhasbeenpointedout in RA, although only in case of concomitant dyslipidemia on Interleukin-17; this cytokine, involved in RA pathogen- [28]; MIA3 protein is involved in leukocyte adhesive inter- esis [18], may accelerate myocardial fibrosis and promote actionswithvascularendothelium,reducesattachment,and atherosclerosis in non-RA animal models [19]. Therefore, promotes migration of monocytes across the endothelium, elevated circulating IL-17 levels have been detected in thus leading to foam cells and fatty streak appearance with patientswithacutecoronarysyndromes[20].InRApatients, vesselwalls[29].Likewisetogeneralpopulation,acidphos- thiscytokineinfluencesmicrovascularfunctionandarterial phatase locus 1∗C allele is associated with CVD events in compliance,thusplayingasignificantroleindevelopmentof RApopulation;astheauthorsstate,thismayresultfromthe endothelialdysfunctionandCVDinthesetting[21]. majorproductionoftheSisoformoflowmolecularweight