2001-2002 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

Chen, YY

Qian, ZM

2001-2002 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishedVoR allowe

PolyU Institutional Repository

????:??? ,?????????????????·??·心脏铁代谢及其相关疾病研究进展陈莹莹　钱忠明　　???????????????。??????????? , ??????-?????????? 、???? 、???? 、??????????? ,?????????? , PKC-β 、p21 ????????????????[ 1] 。??? ,???????????????????。?????????????????????????? , ??????????????????-??? 、??? 、β-???????????????????????。? 、??????? 、???????????????? 3～ 4g。??????????:(1)????????(75%):70%?????????????? ,????????????? , ????? 、????? 、??????????? 。(2)???(25%):????????????????。???? ,????????????:(1)???:???????????? ,???????? ,???????????;(2)?????:?????? , ?????????;(3)?????:????? , ????? , ??????????????????;(4)???????:???????????????????? ,?????????[ 2] ;(5)?????:?????????? , ???????? ATP、AMP ???? ,??????。??????? , ???????????? ,???????-??????????? , ??????????????? , ?????? 、?????????????;???????????? ,????;???????????。??????? ,?????????????? 、?? 、?????????? ,???????? 、??????????。? 、????????????????1.??????:????? , ??????????????????????????????????? ,?????????????(divalent metal transporter 1 ,DMT1)???????(FP)??。????(transferrin , Tf)???????(transferrinreceptor , TfR):???????? , ????????????? , ?? Tf-(Fe3+)2 ?????????? TfR ?? , ???????。TfR??????????? , ????????Tf-(Fe3+)2??? , ?????。???? Fe3+???????? Fe2+, ? DMT1 ?? , ??????。???Fe2+????????? , ?????????????;?????????。??????????????TfR????[ 2] 。????? TfR???? , ??????? ,????????。?????59Fe-Tf???????? ,??????????????(non-transferrin binding iron ,NTBI)?????? Tf-Fe3+? 300 ?。TfR??????????????。????????? , ???????????。??????? 1(Divalent Metal Transporter 1 , DMT1):DMT1 ? 1995 ????????????????????? ? ? , ? ? ? Nramp2 (natural resistance associatedmacrophage protein 2)? DCT1(Divalent cation transporter 1)。DMT1 ??????????????[ 3] 。 DMT1 ??????????(IRE ? non-IRE), ???????????????。??? 3′??????????(iron responsiveelement , IRE), ????? IRE。 ???????? , ??DMT1 ?????????? , ???????????? ,?? DMT1 IRE???????? DMT1 non-IRE。 DMT1 ?? 12 ????????? , ?????????????? ,??????????(?? Fe2+)???[ 3] 。 DMT1 ????????????????? , ??? Fe2+? Tf ???????????????[ 4] 。 DMT1???????????? , ???????????[ 3] 。??????????????? Fe2+???[ 5] 。 DMT1 ??????(?)???????????。???????? ,???????? , DMT1?????? ,??????? , DMT1 ??????。??????(ferroportin , FP):FP ?? MTP1(metaltransporter protein)? IREG1(iron-regulated transporter), ? 2000?????????????????????[ 6] 。? FPmRNA ? 5′??????? IRE??。???? FP???10????。?????????????????????????? FP?? , ??????(Hephaestin ?/?????)???? ,??????????????????。??????????? , ????? FP ?????????。FP??????????? , ?????????????[ 7] 。 FP ??? NADH ??? 、NADHP??? 、???????? , ?? NADP/??????? ,??????????????[ 7] 。???????? FP????·59·???????? 2002 ? 1?? 30 ?? 1 ?　Chin J Cardiol , January 2002 , Vol.30 No.1?[ 8] ,??????????????????????????? ,????????。????(lactoferrin , LF):LF ??????????????。???????? LF1 、LF2 ? LF3 ????????。?????? , LF ???? ,?????????????????????[ 9] 。 LF ? Fe3+??????(?Tf? 300?),? pH ?? 3 ? ,???????? ,???????。?? LF??????????????????????。?????(ferroxidases):??????????????????(ceruloplasmin , CP)???????(hephaestin ,HP)。CP???????? , ????? CP??????????????。?????CP??? ,???? CP????????? CP , ?? CP ?????????[ 10] 。????? ,?? CP????? , ????? CP?????????????。CP ?????????????????? Cu2+;?????? ,??????? Tf ?? , ????????? ,???????。 CP???????????。???? , CP??????? , ?????????。 CP???????????????????? ,?????????。??? CP????????????????????????;?????? CP??????????? ,????????????????[ 11] 。HP?????????? CP?????????? , ???????? ,?????????? ,???????????????[ 12] 。??????? HP ????????[ 8] ,??? HP???????????????。2.??????:??????????(ferritin , FR)??????(haemosiderin)????? , ?????? FR????????。?????????????FR???? 2∶1 , ????????? , ???????? 5∶1。?????? FR? 24 ????? ,???FR?? 34～ 38 ????? ,????? FR?????????? FR。 FR? L?(light type)? H ?(heavy type)????。??? H ?mRNA? L? mRNA????? , ???????????????。???? ,H?????FR???????? ,H ????????? Fe2+?????? FR ,? L??????????????????[ 13] 。?????????????????? CP ???? , ??????????FR?? , ????? HP?????????????。FR???????????????????????。??FR????? , ????? Haber-Weiss ?????????。???? , FR-?????????????????????。???????????????? , ???????????? Ca-ATPase???? , ????? FR???。FR??????????????。??????? ,????? H ?mRNA ? L? mRNA ??? ,?? FR???。???????? , L ? FR?????????[ 14] 。3.?????(iron regulatory proteins , IRPs):IRPs ????????????????? mRNA ???????(iron responsive elements , IREs)?????? , ?????????——— IRP1 ? IRP2 , ?????????????????? mRNA ??????????[ 15] 。 ? IRP ? FRmRNA、??????? mRNA、5-???????(5-aminolevulinate sunthase , ALAS)mRNA ? 5′? IREs ??? , ??????。?? IRP ? TfR mRNA ? DMT1 mRNA3′??IREs ??? ,??? mRNA????。 IRP1 ? IRP2 ??????????? , ?????。?????? , IRP1?????[ 3Fe-4S] ?????????[ 4Fe-4S] ?? , ???IREs ????? ,? IRP1 ???????;?? , IRP2 ?????????? , ????? IREs ?????。 IRP1 ?IRP2?????????? , ?????????(ONOO-)????????[ 16] 。? 、????????1.???(adriamycin , doxorubicin)???????:???????????????????? , ??????????????? 、????????。??????????????? , ??????? DNA?????????。???????????????????? ,???????????????????[ 17] 。?????????????????????????????????。??????? 2 ???????????????? , ??????????????????。?????????`??-??′??? , ?????????????? , ?????????? , ?????-???? , ??Haber-Weiss ????????。 ?????????????????????????。????????????? , ????? , ???????????。??????????????????????? , ????????? , ?????????[ 18] 。 ??????(????)???????????? , ???????????????-????????。? ICRF-187 ???????? ,?????????? ,??????????????? , ????????。2.????-?????:????????????????。??? , ???????????????????? 、??????????? , ?????????-?????。???? , ?????????????????????? , ?????????????-????????????。 Salonen ?????? 1984 ?? 1995 ??2 862?????????????????? , ?????????????????? , ?????????????? 88%。?????? , ???????????·60· ???????? 2002? 1 ?? 30?? 1 ?　Chin J Cardiol , January 2002 , Vol.30 No.1???????。????? ,????????????????? ,????? 27?[ 19] 。?????????????????????????? ,???????????。????????????????:(1)??????:???? 30 min ? , ????? pH ???? 5.9 , ????????????????? ,???(Fe3+)??????????(Fe2+),????????[ 19] 。(2)?????????:????????????????????????????????[ 19] 。???????????? , ???????????? , ????????????-???????????[ 20] 。??????????????? ,?????????????? Haber-Weiss?? ,????????。????? , ???????? ,????????? , ????? , ??????????????? ,??????????????????。3.???????(hereditary hemochromatosis ,HH):HH???????????? , ????????? 、????????????????????。 80%～ 90%???HFE(hereditary hemochromatosis protein)???? C282Y ?? ,HFE ?????? , ??? β2-?????? , ????????[ 21] 。???????? 、?? 、??? 、????。?? 1/3 ????????。?????? HH ?????? ,?????????。??????????? , ???????? ,??????????;?????????;??????????????????。HH ????????????????———???????? , ??????????????????????????? ,???????????????????。??????(?????? , ???)??????????? , ???????????? ,???????????。????????????????。????????????? ,????????????。??? ,???????????????????? ,?????。4.β-?????(thalassemia):β-???????? β-?????????????? , ?? β-???????? ,????α-?????? , ?????????????? ,????????????????? , ???????? ,??????[ 22] 。β-??????????????????? 。?????????????????????????????;??????????? , ????????????????????????????。???????????? 10 ～ 15 ? , ????????????????????????。???????????????????? ,??????????????????? ,??????????????????????。????????? , ?????????? 20?。??? ,???????????????????。????????? , ????????????????? 2 500 ng/ ml , ???????? , ????;??????????????? , ????[ 23 , 24] 。5.????????(coronary atherosclerosis):???????????????????? , ???? 48%。 ????? , ??????(low-density lipoprotein , LDL)??????????????????????。 ??? LDL????????????? ,?????? , ????????????? , ??????[ 25] 。1981 ? , Sullivan??`???′?? ,????? LDL?????????????。???????????????。??????? ,????????????? , ???????????????[ 26] 。?????????????????? , ??????????????????? , ????????????(???????????????)?? ,????????????。????????????????????????。??????? , ???????LDL?????? ,????????。??????????????????????。6.?????????(friedreich′s ataxia, FRDA):FRDA?????????????? ,???? 1∶50 000。?????????????? , ?????? , ?????。???????????? , ????????? , ?????? FRDA?????????。 97%????9 ????? frataxin???? 1 ?????????。 Frataxin???????? , ?????????(??? 、?? 、????)????[ 27] , ??????????。? FRDA?? , ??????????? , ???????? I , II/ III ???????????? , ??? DNA????。???? , ???????? frataxin???? ,?????????? ,??-?????????[ 28] 。? 、????????? , ???????? , ????????????????????????????。 ????????????????-???????????? , ????????? , ????????????????????? ,???????????????? 、??????????????????????? , ??????????????????。?? , ????????????? Tf-TfR??????????? ,?????????????????????????????????。??????????????????????????。?????????????????????????????????。??　?????????????????????????????????·61·???????? 2002 ? 1?? 30 ?? 1 ?　Chin J Cardiol , January 2002 , Vol.30 No.1? ? ? ?1 Boldt DH.New perspectives on iron:an introduction.Am J Med Sci ,1999, 318:207-212.2 Qian ZM , Tang PL , Wang Q.Iron crosses the endosomal membrane by acarrier-mediated process.Prog Biophys Molec Biol , 1997 , 67:1-15.3 Gunshin H , Mackenzie B , Berger UV , et al.Cloning of characterizationof a mammalian proton-coupled metal-iron transporter.Nature , 1997 ,388:482-488.4 Tabuchi M , Yoshimori T , Yamaguchi K , et al.Human NRAMP2/DMT1 , which mediates iron transport across endosomal membranes , islocalized to late endosomes and lysosomes inHEp-2 cel ls.J Biol Chem ,2000, 275:22220-22228.5 Tandy S , WilliamsM , Leggett A , et al.Nramp2 expression is associatedwith pH-dependent iron uptake across the apical membrane of humanintest inal Caco-2 cells.J Biol Chem , 2000 , 275:1023-1029.6 Donovan A , Brownlie A , Zhou Y , et al.Positional cloning of zebrafi shferroportin1 identif ies a conserved vertebrate iron exporter.Nature ,2000, 403:776-781.7 McKie AT , Marciani P , Rolfs A , et al.A novel duodenal iron-regulatedtransporter , IREG1 , implicated in the basolateral transfer of iron to thecirculation.Mol Cell , 2000 , 5:299-309.8 Rotig A , Chantrel-Groussard K , Munnich A , et al.Expression study ofgenes involved in iron metabolism in human tissues.Biochem BiophysRes Commun , 2001 , 281:804-809.9 Arnold RR , Cole MF , McGhee JR.A bactericidal effect for humanlactoferrin.Science , 1977, 197:263-265.10 Linder MC , Moor JR.Plasma ceruloplasmin.Evidence for its presencein and uptake by heart and other organs of the rat.Biochim BiophysActa , 1997, 499:329-336.11 Fox PL , Mukhopadhyay C , Ehrenwald E.Structure , oxidant activity andcardiovascular mechanisms of human ceruloplasmin.Life Sci , 1995 , 56:1749-1758.12 Vulpe CD , Kuo YM , Murphy TL , et al.Hephaestin , a ceruloplasminhomologue implicated in intestinal iron transport , is defective in the slamouse.Nat Genet , 1999 , 21, 195-199.13 Ferreira C , Bucchini D , Martin ME , et al.Early embryonic lethality ofH ferritin gene deletion in mice.J Biol Chem , 2000 , 275:3021-3024.14 Kwak EL , Larochelle DA , Beaumont C , et al.Role for NF-kappa B inthe regulation of ferritin H by tumor necrosis factor-alpha.J Biol Chem ,1995, 270:15285-15293.15 Ward RJ , Kuhn LC , Kaldy P , et al.Control of cellular iron homeostasisby iron-responsive elements in vivo.Eur J Biochem , 1994 , 220:927-931.16 Nulton-Persson AC , Szweda LI.Modulation of mitochondrial function byhydrogen peroxide.J Biol Chem , 2001 , 276:23357-23361.17 Bristow MR , Mason JW , Billingham ME , et al.Dose-effect andstructure-function relationships in doxorubicin cardiomyopathy.Am HeartJ , 1981, 102:709-718.18 Trost LC , Wallace KB.Adriamycin-induced oxidation of myoglobin.Biochem Biophys Res Commun , 1994 , 204:30-37.19 Voogd A , SluiterW , van EijkHG , et al.Low molecular weight iron andthe oxygen paradox in isolated rat hearts.J Clin Invest , 1992, 90:2050-2055.20 Ambrosio G , Zweier JL , Jacobus WE , et al. 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心脏铁代谢及其相关疾病研究进展

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