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  O 2 2 H Vascular Health and Risk Management Dove  press open access to scientific and medical research Open a ccess Full Text a rticle O R ig inal Resea R c H Vasa vasorum anti-angiogenesis through 2 2 , HiF-1 α , n F- κ  B, and i n O s  inhibitionb mangosteen pericarp ethanolic extract! Garcinia mangostana l inn in hpercholesterol- diet-given Rattus norvegicus #istar strain  Titin a ndri #ihastuti 1 Background: Oxidative stress in atherosclerosis produces H O and triggers the activationof  2 2 $%anggan s argo&o 2 a s'andar  T%o'ropra&iro ( n ur )ermatasari * +ohammad a ris #idodo * seto&ati s oeharto * 1 $epartment o Biomedical, nuclear factor kappa beta ! #κ$% and increase of inducible nitric oxide s&nthase i!O'%()he formation of vasa vasorum occurs in atherosclerosis( Vasa vasorum angiogenesis ismediated b& V*+ R#, and upregulated b& h&poxia#inducible factor#,α H- #,α%( )he ne.l&formed vasa vasorum are fragile and immature and thus increase pla/ue instabilit&( -t isnecessar& to control vasa vasorum angiogenesis b& using mangosteen pericarp antioxidant()his stud& aims to dem# onstrate that mangosteen pericarp ethanolic extract can act as vasavasorum anti#angiogenesisthrough H O 0 H- #,α0 ! #κ$0 and i!O' inhibition in rats given a h&percholesterol diet( +edical Facult, Bra&i%aa niversit, 2 2 +alang, indonesia. 2 $epartment o c ardiolog, +edical Facult, Bra&i%aa niversit, +alang, i ndonesia. ( $epartment o e ndocrinolog,+edical Facult, a irlangga niversit, surabaa, indonesia. * $epartmento )harmacolog, +edical Facult,Bra&i%aa niversit, +alang, i ndonesia Methods: )his .as a true experimental laborator&0 in vivo posttest .ith control groupdesign0.ith 21  Rattus norvegicus istar strain rats divided into five groups normal group0h&percho# lesterol group0 and h&percholesterol groups .ith certain doses of mangosteen pericarp ethanolic extract3 2110 4110 and 511 mg6kg bod& .eight%( )he parameters of thisstud& .ere H O measured b& using colorimetric anal&sis0 as .ell as ! #κ$0 i!O'0 andH- #,α0 .hich .ere measured b& using immunofluorescence double staining and observed.ith a confocal laser scanning microscope in aortic smooth muscle cell( )he angiogenesis of vasa vasorum .as /uantified from V*+ R#, level in aortic tissue and confirmed .ithhematox&lin and eosin staining( Results: 7nal&sis of variance test and 8earson9s correlation coefficient sho.edmangosteen pericarp ethanolic extract had a significant effect   P  0 1(1:% in decreasing vasavasorum angio#genesis through H O 0 H- #,α0 ! #κ$0 and i!O' inhibition in h&percholesterol#diet#given  R. 2 2 norvegicus istar strain( Conclusion: Mangosteen pericarp ethanolic extract 511 mg6kg bod& .eight is proven todecrease vasa vasorum angiogenesis( 'imilar studies .ith other inflammator& parameters areencouraged to clarif& the mechanism of vasa vasorum angiogenesis inhibition b& mangosteen pericarp ethanolic extract(  Keywords: mangosteen pericarp ethanolic extract0 H O 0 H- #,α0 ! #κ$0 vasavasorum 2 2 angiogenesis0 h&percholesterol c orrespondence/ Titin a ndri #ihastuti $epartment o Biomedical, +edical Facult o Bra&i%aa niversit, Veteran street, +alang, east 0ava, 1*, i ndonesia Tel ; 2 3134 141325Fax ; 2 (*1 *5email di'titin6ahoo7com Introduction Mortalit& from coronar& heart disease <HD% caused b& atherosclerosis is increasedsharpl& in both industrial countries and developing countries( , 8revalence of atheroscle# rotic <HD has been increasing &earl& and has been declared b& theorld Health Orga#ni=ation HO% as a global threat( 2 -t is estimated that ,(> billion people0 or one#third submit your manuscript  8 && & 7d o v ep ress7com Vascular Health and Ris' +anagement 241*/14 2(9(1 523 Dove    press http: d! doi org#$ 2#%&'(RM )*#&3* : 241* #ihastuti et al7 This &or' is published b $ove +edical )ress ;imited, and licensed under <reative <ommons =ttribution 9 >on <ommercial !unported, v(74 ;icense7 The ull terms o the ;icense are available at http/??creativecommon s 7o r g?licenses? b -nc?(74 ? 7   >o n - c o mme r ci a l   uses o ,    the &or' are permitted &ithout an ,  u r t he r permission ,  r o m   $ove +edical )ress ;imited, provided t   he &or' is properl attributed7 )ermissions beond the scope o ,    the ;icense are administered b $ove +edical )ress ;imited7 @ n ,  o r m a t i o n   o n ho& to reAuest permission ma be ound at/ http/??&&&7d o vepres s 7com?permission s 7php  #ihastuti et Dove  press #2 submit your manuscript  8 && & 7d o v ep ress7com   Vascular Health and Ris' of the .orld9s population0 are affected b& this disease( 2 -n-ndonesia0 morbidit& and mortalit& from <HD are likel& toincrease and the mortalit& rate has reached :1?( 2 Risk factors for atherosclerosis include d&slipidemia0free radicals0 endothelial d&sfunction0 and inflammation( @ -ncreased levels of cholesterol in blood0 especiall& lo.#densit& lipoprotein ADA% cholesterol0 is harmful becauseof the peroxidation process auto#oxidation% of lipids.hich are exposed to ox&gen( Aipid peroxidation is achain reactionthat continues to produce reactive ox&gen species RO'%such promoter h&poxia response element sites that regulate classics genes for responsiveness to h&poxia( ,, )he possible role of H- #,α in atherosclerosis is sup# ported b& the presence of intrapla/ue angiogenesis0 .hichis an implication of some H- #responsive genes in ath#erosclerosis0 such as vascular endothelial factor V*+ %0 endothelin#,0 and matrix#metalloproteinase#2( ,@B,: V*+ binds to t&rosine kinase receptors and becomes V*+ receptor#, V*+ R#,%0 .hich is also kno.n as lt fms#like t&rosine kinase#,%( V*+ R#, is expressed in earl& vascular as OH C 0 RO0 and h&drogen peroxide H O %( 4 H Ocausesdevelopment and postnatal angiogenesis( V*+ R#, is also 2 2 2 2 nuclear factor kappa beta ! #κ$% activation( ! #κ$ is atranscription factor that pla&s an important role in control#ling various biological effects such as inflammation0 immune defense mechanism0 cell proliferation anddifferentiation0 tumorigenesis0 and cell apoptosis( :  ! #κ$ pla&s an important role in atherosclerosis because of thechronic inflammator& process that occurs throughoutatherosclerosis( D  ! #κ$ activation products initiate the process of atherosclerosis .ith endothelial d&sfunction0 occurrenceof platelet adhesion0 and the migration and proliferationof smooth muscle cells( E -nducible nitric oxide s&nthasei!O'% expression is increased in macrophages andsmooth muscle cells at the earl& and advanced stages of athero# sclerotic lesions( -nflammation pla&s a crucialrole in the development of atherosclerotic lesionsaffecting coronar& arteries( i!O' pla&s an important rolein inflammation through the fast and high production of  prostanoid and !O0 both of .hich have proatheroscleroticeffects( 5 7ctive metabolism of cells happens in inflammation()he metabolism of active cells enormousl& increases thedemand for ox&gen and the reduction of ox&gen suppl&0finall& resulting in h&poxia( > )he rise of h&poxia that takes place in vessel .alls is also caused b& the thickening of arterial .alls in atherosclerosis0 .hich disturbs thediffusion of ox&gen( ,1 H&poxia is strongl& associated .ithangiogenesis and formation of thrombus( )he effect of h&poxia is mediated b& macrophage0 .hich infiltrate thethrombus( 7 macrophage is a cell that has the abilit& toimmediatel& alter not onl& anaerobic metabolism but alsoaerobic metabolism gl&co# l&tic turnover%( )his elevatesthe ox&gen demand( ,, H&poxia promotes the adaptation of cells through the activation of h&poxia#inducible factor#,αH- #, α %(H- #,α is a transcription factor that regulatesgl&col&sis0 angiogenesis0 and cell survival( ,2 H- #,α innormal ox&genconditions is unstable and cannot be detected due toh&drox&#  Vasa vasorum anti-angiogenesis b Garcinia Dove  press #3 Vascular Health and Ris' submit your manuscript  8&& & 7d o v ep ress7com   expre   ssed in inflammator& cells such as monoc&tes andmacrophages0 .hich coordinate inflammation and becomean earl& marker of pathological angiogenesis associated.ith atherosclerosis( ,2 Research conducted b& 'luimer etal , in2115 suggested that h&poxia is strongl& associated .ithangiogenesis and thrombus formation( 7therosclerosissho.s the process of vasa vasorum angiogenesis to beextensive0 fragile0 and immature0 and associated and insta# bilit& of atherosclerotic pla/ue( ,E0,5 )hevasa vasorum become interesting to discuss for their uni/ue function0 because the vasa vasorum are vesselssuppl&ing blood to the vessels0 or in other .ords0 vesselslocated inside vessels( ,> <ollection of evidence related to pla/ue vasa vasorumangiogenesis and its contribution to the progressivit& of atherosclerosis and development of lesion instabilit& dem#onstrates the importance of controlling angiogenesisthrough anti#angiogenic agents( 21 $ecause of RO'involvement from the beginning of pathogenicit& of atherosclerosis0 .hen the vasa vasorum angiogenesismechanism is involved0 the use of antioxidant as an anti#angiogenic agent is an essential consideration(Mangosteen pericarp extract  Garcinia mangostana Ainn% is one potential antioxidant agent( $ioactive contentof the skin of mangosteen has anti#inflammator&0antioxidant0 and antihistamine effects0 as .ell as other  pharmacological activities( 'ome of the maFor compoundsin mangosteen skin that are reported are xanthones( 2, Mangosteen pericarp extract is proven to inhibit ! #κ$activation in rat models .ith administration of ah&percholesterol diet( 22 Mangosteen pericarp extract possess high antioxidant activit& that inhib# its cellular damage caused b& RO'0 so ! #κ$ remains in an inactivestate in c&toplasm( Research to prove .hether or notmangosteen pericarp ethanolic extract M8**% ma& prevent vasa vasorum angiogenesis through the inhibitionof H O 0 H- #,α0 ! #κ$0 and i!O' expressions in istar strain 2 2 lation( -n h&poxic conditions0 H- #,α is stable and undergoes translocation from c&toplasm to nucleus and  binds to specific  Rattus norvegicus rats .ith h&percholesterol diet admin#istration has not &et been undertaken( )he purpose of this
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