KL ChineseJournalofPathophysiology 2013,29(2): [] (2013) !"#$%&',,, (!"#$%&' %, ) Rolesofmitochondrialdysfunction

Transcription

1 KL ChineseJournalofPathophysiology 2013,29(2): [] (2013) !"#$%&',,, (!"#$%&' %, ) Rolesofmitochondrialdysfunctionincardiovasculardiseases XIONGYan,ZHANGMei,CHENFei,FANGWei jin (GuangzhouResearchInstituteofSnakeVenomandDepartmentofPharmacology,GuangzhouMedicalColege, Guangzhou510182,China.E mail:xiongyan2001@yahoo.com) [ABSTRACT] Mitochondriaareimportantorganelesofenergygenerationineukaryocytesandplayapivotalrolein celcalciumhomeostasis,signaltransductionandapoptoticregulation.theposiblecausesleadingtomitochondrialdys functionincludeoxidativestres,ca 2+ disorder,reductionofmitochondrialbiosynthesisandmitochondrialdnamutations, alofwhicharealsocloselyrelatedtothedevelopmentofcardiovasculardiseases.understandingthemitochondrialdysfunc tionanditsimportantroleincardiovasculardiseasesareverysignificantforelucidatingthemechanismsofcardiovascular diseases. [ (] ()*;()*+,-.;/01 [KEYWORDS] Mitochondria;Mitochondrialdysfunction;Cardiovasculardiseases [)*+,] R363 [-./0] A doi: /j.isn / :; 7 <=>,3?@ABC7DE, 3 7 PQR,/01 7 2SRTJ UV WXY, 1700Z[3\]/ 01 ;^_ D 300[3\]/0 1,`a\bc 7 41% [1] 0 / 0 - / 7/01 ^,?7=@ Z7%& I,()*+, -. /01,, %& ()*+,-._/01 =@=> 7, I/01 7= N 1!1 &"# 1.1 ', _ 9 b ()* F 7 ) F, ()* 4 7() *, 7 / 7[, ], 7, /, D,,( ) * Z, ` * 7 40% ()*_ 7! "#7, $!] A%7 & 1.2 ()*, R', ()*, +, 7,-./(ATP) NADH+H + FADH 2 ()* # 2) , 8_ 2)Ⅰ Ⅱ Ⅲ Ⅳ9: ; () *,^ _()* # < ;,=()* <>(mitochondrialtransmem branepotential);()* 7 8 2)Ⅴ F BCDE_()* <> 7, 2) V F 1 ATP,=,- _FGHIJ, [] [ ] [ ] (No ;No ) Tel: ;E mail:xiongyan2001@yahoo.com

2 MN O (uncouplingproteins,ucps)./- >* (ade ninenucleotidetranslocator,ant)@a, 7,, ]2 ATP^M,7 HP=; ()*, -O (reactiveoxygenspe cies,ros)7 ';_()* 3 2)Ⅱ Ⅲ Ⅳ7<867,?7TT Q - Uc 7V 1 <87WX Y 3, 8,C'V7 1 <8 Z[8(superoxideanion,O 2) - \()*<867 < ]^B, WX7W _`a, Z[8@ QR;\()*<867< RbB, WX7 QZ, Z[8@ QR;, ()*, c 7 ),()*U_ ASN 9 ()* Ca 2+ X 2 H 2 H;%& 7 H Ca 2+ *(uniporter);,?()* <>7< ; Ca 2+ ()*,^ 8 [8;,()*7 <> ()* Ca 2+ 7 E ]()*_ > 7 Ca 2+ N,,NB Ca 2+ : 7L Ca 2+, S Ca 2+ Ca 2+ 7 ; M Ca , ^ Ca ()* E7 Ca 2+ U, Ca 2+ 7 ()* F 0 F 1 ATP2 MN# 2 (nitricoxidesyn thase,nos) 7AS;,- ATP7@)2, *, 7 ()*7 Z b 8, 3 #7 C(cytochromeC, CytC),\, b A 8 1(apoptoticproteaseactivatingfactor1,Apaf 1) 2 = caspases5, b; () *_ b,()*u _ Q Z M - /7@)2 7 2!"#$% 2.1 ()*+,-. :(1)ATP2 ] :()* AS MN UCPs ANT 7 8 ()* <>, ^ ATP2 ] ;(2)ROSQZ: 3< 867]^ QZ / A S ROS QZ;(3)Ca 2+ :()* < > ()* Ca 2+ ] ()* Ca 2+ QR Ca 2+, # Ca 2+ AS7 9 ;(4) b: ()* S L M (mitochondrialpermeabilitytransition pore,mptp) mptp S CytC, A caspase5, b 2.2!"#$ %&'! ( ) ()* ', ROS \ 7 ;,\()* ) (manganesesuperoxidedis mutase,mn SOD) ) 7, ()* ROS@ QZB, (oxidativestres) ()* Z[ 8@ QZB,U # 7 - Z[8(per oxynitrite,onoo - ), (nitrosative stres) ()* AS,]^ 37<867,QR U M UCPs [2] UCPs >]()* 7#4 [8 N 7, () * 7 H 8, ^ ()* <>, -,- O,] ATP2 ; B UCPs ] ()* ROS@ ;, 7 UCPs 7#,M] ()* ROS7@ ; 7 UCPs ()* +,-.7 8,UCPs_()*+,-. U ()* DNA 7 2 ROS M ROS,# ROS 7 ROS (ROS inducedrosrelease,rirr) [3] RIRR _ J = mptp Z[8 N, ()* <> ROS, ()*7 RIRR, RIRR, ( )*+, # 2 b *+, -.!/ )0 ()* Ca 2+ Ca 2+ ;()*,- Ca 2+, 3 <867 7()* <> ]()* Ca 2+ 7 ;()* 7 Ca 2+,,- AS^ ATP2 ;,! 3

3 366 2)AS7 ()* <> 7 8 mptp ()* DNA" L ()* Ca 2+,()* Ca 2+ #*$ N Ca 2+ X 2 ()* Ca 2+ %7c & %&'N, / ()*+,-. mptp 7^ Ca 2+ * [4] ;, mptp A 7/ ()*+,-., Ca 2+ * S ()*@)2 ATP7, ; ()* DNA( )( )*@)2 3?#*+ ()* C Ⅰ(cytochromeCoxidasesubunitⅠ, COXⅠ) β actin,- 7. )() * DNA( [5] /0 ) *Q1) A * γt A 8 1α(peroxisomeproliferators activa tedreceptorgammacoactivator1alpha,pgc 1α) ( )*@) (nuclearrespiratoryfactor1,NRF 1) ()* 8 A(mitochondrialtranscriptionfactorA,mt TFA), ()* 7,() *@)2 QR [6] /0 NOS(endothelial NOS,eNOS)2 7 NO PGC 1α ()*@)2 7 8;,AMP A (AMP activatedproteinkinase,ampk) ( )*@)2 7 8 #;\ *, 23 DB, ATP/ADP 4,AMPB C 5, AMPK ()*,QR()*@)2, + [7] ;,U Z 9 ()*@ )2 Ca # 6 9 MN 7,? Ca 2+ camp NO ATP/AMP 47KL, PGC 1α7 AS, ()*7@)2 8Z%&/ I,9: ; N 3 )7 / ()* DNA,- PGC 1α "IJ, ) ()*@)2 ; _ 3 < B PGC 1α N()* ;, ()*@)2 ], ()*+,-.7== ; / ()*2 ] >2? =/01 7 L : -. ; <!/ () ()* S L(mitochondrialpermeabilitytransition,MPT) ( )* S"QR, ] mptp ' mptp >]()* Z ' S 2MN, 8 8 _ 1.5kDMJ7B 8 H + Ca 2+ N C mptp ()* 7< SZ[8 N 7./- >8 7C D (cyclophilind,cyp D) #G 8 D E 4 *,- - CyP D A7 *;, A, CyP D S 2, mptp, / 0 / [8] 8Z ()* <> ()* ATP3, [ -QR,- " mptp, Ca 2+ _ mptp = R ;mptp7, / SZ7AS, S 1 J,mPTP F 9S, G] Ca 2+ ()* MH ()* 7 ; J,mPTP < H7aB 9S, ()* 7 H + A,()* IJK, ()* <>LM, -,- O, ATP2 N ;()*,Uc 3, ; O 5,()* IJ,& ()*, 7 C b 8, A caspase b \b DNA=:>?@;ABCD". ()* #W S, 7P6) ( ) * DNA(mitochondrial DNA,mtDNA),,QRST UVW ( )*, ] mtdna XY7, DNA 2 7, ]()* 3, AS 7,,mtDNAK ^ 2 [5],R mtdna 7 X, mtdna 2 "L; mtdna (8,'M mtdna"lz [N 7+,,- (oxidativephos phorylation,oxphos) ; mtdna "L \ ][ #^_.B= ()* +,-. S 7?, = ()* "L7_. 3!"#$%&' 3.1 E & (atherosclerosis) /01 \b7

4 367 c 2 7== ; `a01b, c, 01C Q1N J L 7 ()*+,-.B S 3 Z7 ROSMN[ 7 mtd NA 2 "L 7=@=> [10 11] D % & I, (oxidativedlow densitylipoprotein,ox LDL)_ 7=@=> ;( ) 7 ROSN 7 ox LDL N 7 Ox LDL ()* A S, ()* 3<867]^,QR ROS@, S1, [12] apoe -/- # # E7 ), 0 7BCJ QR, L %&=,apoe -/- Mn SOD(SOD 2 )AS,( )* DNA QR, ] 7 ;apoe -/- ()* Q, LIJR [13] ;, apoe -/- -SOD +/- 2 7%&J,()* ROSQR 7,^ UQR * 87 S [14] 01 S? "L (ataxiatelangiectasiamutated,atm) # DNA N 7, B mtdna7@)2 ( & % &= [10 11],apoE -/- ATM +/- _ ( = 0?, IJR<7, L 701C c DNA QZ,()* DNA( ],ROS mtdna SR )QR G DNA +, -. 7 mtdna 2 R < apoe -/- MN =?,mptp B ()* <>JK ;^ mptpab, ()*, b L, 7=@ => >', ()*+,-.,_ 7 = ;()*+,-.,R< 7=@ =>;^ mtdna +,-., 7 c 3.2 F 0 (hyperten sion) O # 7/01 01 Q 01b S LSMN01C Q1 0 7 L Z7%& I,()*+,-. 0 Z[8 A 2 7 NO, S01 +,,01 QR,0 5 UCP2 Z S KL 7 ( ) *, - O 0 [15] ;Bernal Mizrachi %&=,C UCP1 701C 7dIJ5 0 QR0 AS,()*, %MN()* DNA"L N 0 0 S/ 7 ' 0,01 I(angiotensin I,Ang I)_ 0 7=@=>,AngI ()*AS A NO, 01 +, [16] ; 01 Ang I * F 0, IJK ()*+, ()*+,-.U 0 7+, Chan [17] %&J,_=S 0 D 7` 8 ()* 7 ROS@ QR, ()* AS ; T Q10K ()*<86 7+,,IJ C" 0 ;^ <8673, IJ5 C" 0,()* Z S ()* trna "L 0 7 = R ^()*+,-. c=s 0 7,Wang [18] # D P6 0 7 P6 =,()* trna Ile 4263A>G" L ()*, ()* P6S,%&= 0 E_IJ7 P6 ;& 7%& # H, P67()* trna"l 7()*+, -. c=s 0 7= [19] M%& ROSQR ATP@ ] % MN()*<8673 AS ()*+,-._ 0 7=@=>,Q M,( )* Z S ()* trna "L 0 =, P67()* "L' 7()*+,-.S H c=s GHI -JKLMN / 0 (ischemia reperfusioninjury) ] S/ \7, / / +, (/ ),GL

5 368 /, / \ b ; ()*, -. / 0 7 [20], ()* ATP@ 7 ROS Ca 2+ % mptp S [8] 0/ 7 ROS / 0 7 c,^()* / ROS7 #GI ROS QZ ()*7 X, ^ ()* < >, ()* ATP2 -.; #GI()*+, Z7 ROS, NB Q, 2()* 7 S, <86 73 AS7 # J, ^ S1,& / b \ [24] Shc-/- _/ 0 IJ] /, Z7 ROS / 0 7c # [21] ;, / 0 7 ; D %& I,/ 0 B Ca 2+ % / 0 7 c,^ ;ROS KL()* 7 S, Ca 2+?: ; ()*, M BS,- 7 H ]()*,, - -.,ATP@ ] ^ # QZ;( / ATP S Na + ASJ, Na + 5, A Na + -Ca 2+ 8, Ca 2+ QZ^RP Ca 2+ % [8] & %& =,_ 0 / mir 214 Na + -Ca mrna,, 7 \b 9,= [22] G%&, ()* Ca 2+ #, / 0 7 # QR Ca 2+ %,()* mptp S S _ 0 = mptp D 8 ()*, () * <>LM, B Z b 8( CytC ) b \b [8] %& H, *A 7 / 0 ()* mptp7 ^H [23] 0 / 7 ()* mptp [24] ()* / 0 ( ) * mptp7 S [25], A mptp 7 ), / 0 = [8] ; mptp / 0 7 # [26] >',K ()*+,,] ( )* # ()* mptp7 " 0 / GO / (heart failure) / 0, / 7 ] ^, * 7 ; / \ 0 / Z/01 => 7 ()*+,-. / 7 * _MJ GI: ()*, -._/ =@=> ;_ 3 Z ) 7%& I,/ B/ ()*E _ <8673,- 2) +, ; _/ ) %&=,/ ()* 2) IVASIJ] ; 2) I 2) I7AS [27] ;GKL ()* ATP2 ], U ()* ROS@ QR;/ ()*, -.R / +, /+,7 ;ROS / 7 c, / +,7 S] / 9 ;& %&=, _ IJ/ / 7 3 / ()* OXPHOS 3 2) -, 7,^_ 7 _ ()* 7 ;G HR()*+,-. _/ [28],()*@ )2 / 7=@=> _ 7H S / % & I,/ PGC 1α NRF 1 mttfa ()*@)2 8 J,()* DNA( ;GL () *@)2 ], ()*,- MN -,, / 7=> [29] Sebastiani 'N 7 %&,/ B/ mtdna ()*Q1Q R, 7 & 7%& # I,()*@)2 -. ]/ 7=@,_ S/,()* DNA 3 / mtdna, / 9 [30],()*@)2 7KL / B/ L 7c #, / B/()*7 # L ; / - +R 70%7, +,^/ B /7 ) - L ; - 7DE 7 SQ R, # / ( -. /, S

6 369 1 T R/ 7=>,Neubauer 7/, 3 7 ; / 7 G K / 7, + >',()* / B 8 7, / B L 7 ;, ST ()*, +,7 S, ) ] C / ()*_ 9 MN Ca 2+ b "= 7,()*7W S^ #^P6!,,()*+, _@*A 7 ()*+,-.7 KZ ;,/01 B () *+,-.7= " [31 32] ; %&7 F,()*+,-._/01 7 T>C 4#TJ, $/01 7%& [2 3 -] [1] HuSS,KongLZ,GaoRL,etal.Outlineofthereporton cardiovasculardiseaseinchina,2010[j].biomedenvi ronsci,2012,25(3): [2] El KhouryTG,BahrGM,EchtayKS.Muramyl dipeptide inducedmitochondrialprotonleakinmacrophagesisaso ciatedwithupregulationofuncouplingprotein2andthe productionofreactiveoxygenandreactivenitrogenspecies [J].FEBSJ,2011,278(17): [3] BiaryN,XieC,KaufmanJ,etal.Biophysicalproperties andfunctionalconsequencesofreactiveoxygen species (ROS) inducedrosreleaseinintactmyocardium[j].j Physiol,2011,589(Pt21): [4] YaranaC,SripetchwandeeJ,SanitJ,etal.Calcium in ducedcardiacmitochondrialdysfunctionispredominantly mediatedbycyclosporinea dependentmitochondrialper meabilitytransitionpore[j].archmedres,2012,43 (5): [5] ShokolenkoI,VenediktovaN,BochkarevaA,etal.Oxi dativestresinducesdegradationofmitochondrialdna [J].NucleicAcidsRes,2009,37(8): [6] ShengB,WangX,SuB,etal.Impairedmitochondrial biogenesis contributes to mitochondrialdysfunction in Alzheimer sdisease[j].jneurochem,2012,120(3): [7] LiL,MühlfeldC,NiemannB,etal.Mitochondrialbio genesisandpgc 1αdeacetylationbychronictreadmilex ercise:diferentialresponseincardiacandskeletalmuscle [J].BasicResCardiol,2011,106(6): [8] PennaC,PereliMG,PagliaroP.Mitochondrialpath ways,permeabilitytransitionporeandredoxsignalingin cardioprotection:therapeuticimplications[j]. Antioxid RedoxSignal,2013,18(5): [9] GordonLI,BurkeMA,SinghAT,etal.Blockadeofthe erbb2receptorinducescardiomyocytedeaththroughmito chondrialandreactiveoxygenspecies dependentpathways [J].JBiolChem,2009,284(4): [10] MercerJR,ChengKK,FiggN,etal.DNAdamagelinks mitochondrialdysfunctiontoatherosclerosisandthemeta bolicsyndrome[j].circres,2010,107(8): [11]ChistiakovDA,SobeninIA,BobryshevYV,etal.Mito chondrialdysfunctionandmitochondrialdnamutationsin atheroscleroticcomplicationsindiabetes[j].worldjcar diol,2012,4(5): [12] RoyChowdhurySK,SangleGV,XieX,etal.Efectsof extensivelyoxidizedlow densitylipoproteinonmitochon drialfunctionandreactiveoxygenspeciesinporcineaortic endothelialcels[j].am JPhysiolEndocrinolMetab, 2010,298(1):E89 E98. [13] DevarajanA,BourquardN,HamaS,etal.Paraoxonase2 deficiencyaltersmitochondrialfunctionand exacerbates thedevelopmentofatherosclerosis[j].antioxidredox Signal,2011,14(3): [14] HarisonCM,PompiliusM,PinkertonKE,etal.Mito chondrialoxidativestressignificantlyinfluencesathero genicriskandcytokine inducedoxidantproduction[j]. EnvironHealthPerspect,2011,119(5): [15]ChanSH,WuCA,WuKL,etal.Transcriptionalupregu lationofmitochondrialuncouplingprotein2protectsa gainstoxidativestres asociatedneurogenichypertension [J].CircRes,2009,105(9): [16] WidderJD,FraccaroloD,GaluppoP,etal.Atenuation ofangiotensin I inducedvasculardysfunctionandhyper tensionbyoverexpresionofthioredoxin2[j].hyperten sion,2009,54(2): [17] ChanSH,WuKL,ChangAY,etal.Oxidativeimpair mentofmitochondrialelectrontransportchaincomplexesin rostralventrolateralmedulacontributestoneurogenichy pertension[j].hypertension,2009,53(2): [18] WangS,LiR,FetermannA,etal.Maternalyinherited esentialhypertensionisasociatedwiththenovel4263a >GmutationinthemitochondrialtRNA Ile geneinalarge HanChinesefamily[J].CircRes,2011,108(7): [19]QiuQ,LiR,JiangP,etal.MitochondrialtRNAmuta tionsareasociatedwithmaternalyinheritedhypertension intwohanchinesepedigrees[j].hummutat,2012,33 (8): [20] PereliMG,PagliaroP,PennaC.Ischemia/reperfusion

7 370 injuryandcardioprotectivemechanisms:roleofmitochon driaandreactiveoxygenspecies[j].worldjcardiol, 2011,3(6): [21]CarpiA,MenabòR,KaludercicN,etal.Thecardiopro tectiveefectselicitedbyp66 Shc ablationdemonstratethe crucialroleofmitochondrialrosformationinischemia/ reperfusioninjury[j]. Biochim BiophysActa,2009, 1787(7): [22]AuroraAB,MahmoudAI,LuoX,etal.MicroRNA 214 protectsthemouseheartfrom ischemicinjurybycontrol lingca 2+ overloadandceldeath[j].jclininvest, 2012,122(4): [23] BopasaJC,EghbaliM,ToroL,etal.Anovelestrogen receptorgper inhibitsmitochondriapermeabilitytransi tionporeopeningandprotectstheheartagainstischemia reperfusioninjury[j].am JPhysiolHeartCircPhysiol, 2010,298(1):H16 H23. [24]LuN,SunY,ZhengX.Orientin inducedcardioprotection againstreperfusionisasociatedwithatenuationofmito chondrialpermeabilitytransition[j].plantamed,2011, 77(10): [25]OngSB,SubrayanS,LimSY,etal.Inhibitingmitochon drialfisionprotectstheheartagainstischemia/reperfusion injury[j].circulation,2010,121(18): [26]JavadovS,KarmazynM,EscobalesN.Mitochondrialper meabilitytransitionporeopeningasapromisingtherapeutic targetincardiacdiseases[j].jpharmacolexpther, 2009,330(3): [27]RoscaMG,VazquezEJ,KemerJ,etal.Cardiacmito chondriainheartfailure:decreaseinrespirasomesandox idativephosphorylation[j].cardiovascres,2008,80 (1): [28] LemieuxH,SemsrothS,AntreterH,etal.Mitochondrial respiratorycontrolandearlydefectsofoxidativephospho rylationinthefailinghumanheart[j].intjbiochemcel Biol,2011,43(12): [29] FaerberG,Bareto PereiaF,SchoepeM,etal.Induc tionofheartfailurebyminimalyinvasiveaorticconstric tioninmice:reducedperoxisomeproliferator activatedre ceptorγcoactivatorlevelsandmitochondrialdysfunction [J].JThoracCardiovascSurg,2011,141(2): ,500.e1. [30] KaramanlidisG,Bautista HernandezV,Fynn Thompson F,etal.Impairedmitochondrialbiogenesisprecedesheart failureinrightventricularhypertrophyincongenitalheart disease[j].circheartfail,2011,4(6): [31]% &,',,. b< 7 / L KL,2012, 28(8): [32](),* +,*,,,.HSP90 7 Akt()* >- IGF 1. E/7 KL,2012,28(10): 櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆櫆 ( 360 ) /$%& & A%7 9 # Rath [6] 7& %& RKIP 071 (pocket) Raf 1,- 7 N 2, ^ ERK 7,- RKIP ERK 9 7 _ N 7%&,"/ H _G RKIP ERK 9 7 = R 7 ^Q1N _ 7 => 7 H %&= _ D RKIP7 ], H7 > RKIP7 SJ,^ p ERK1/2_ D 7 H7 >QR, H RKIP 7] MN p ERK7 QR, 7 > [2 3 -] [1] YeungK,SeitzT,LiS,etal.SuppresionofRaf 1kinase activityandmapkinasesignalingbyrkip[j].nature, 1999,401(6749): [2] ToyodaM,SuzukiD,HonmaM,etal.Highexpresionof PKC MAPKpathwaymRNAscorelateswithglomerularle sionsin human diabeticnephropathy[j].kidneyint, 2004,66(3): [3] SakaiN,WadaT,FuruichiK,etal.Involvementofextra celularsignal regulatedkinaseandp38inhumandiabetic nephropathy[j].amjkidneydis,2005,45(1): [4] cc,,(,.erk1/2 9 _ 7 KL,2007, 23(9): [5] ZengL,ImamotoA,RosnerMR,etal.Rafkinaseinhibi toryprotein(rkip):aphysiologicalregulatorandfuture therapeutictarget[j].expertopinthertargets,2008,12 (10): [6] RathO,ParkS,TangHH,etal.TheRKIP(Raf 1Kinase InhibitorProtein)conservedpocketbindstothephospho rylatedn regionofraf 1andinhibitstheRaf 1 mediated activatedphosphorylationofmek[j].celsignal,2008, 20(5):