HIF-1α基因C1772T/G1790A的单核苷酸多态性与HIE及HIE所致的脑性瘫痪的相关性研究
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摘要
目的:探讨缺氧缺血性脑病及缺氧缺血性脑损伤所致的脑性瘫痪与HIF-1α基因C1772T/G1790A的单核苷酸多态性的关系,以便在围生期进行早期干预,减少缺氧缺血性脑病和缺氧缺血性脑病所致脑性瘫痪的发病率。为新生儿缺氧缺血性脑病防治找到更好的理论根据。
对象与方法:1.研究分为三组:A组:新生儿缺氧缺血性脑病患儿78例,根据HIE临床表现程度分级,轻度HIE患儿38例、中度HIE患儿26例、重度HIE患儿14例;B组:正常对照100例;C组:新生儿缺氧缺血性脑病所致脑性瘫痪患儿92例,根据既往HIE临床表现程度分级,轻度HIE患儿16例、中度HIE患儿45例、重度HIE患儿31例;2.分别抽取患儿及正常新生儿外周静脉血,参照试剂盒说明分别提取基因组DNA;3.应用聚合酶链反应(PCR)扩增目的基因346bp, 4.PCR产物酶切及电泳。
结果:1.A、B、C三组的孕龄、出生体重、性别差异及喂养方式无显著差异性(P>0.05);2.A组HIF-1α基因1772CT基因型所占较多(30.77%),B、C组HIF-1α基因1772CT基因型所占较少,分别是18%、18.57%,A、B、C三组HIF-1α基因C1772T/基因型分布有显著性差异(P<0.05),A组组内轻度、中度、重度HIE患儿比较HIF-1α基因C1772T/基因型分布无显著性差异(P>0.05),C组轻度、中度、重度HIE患儿比较HIF-1α基因C1772T/基因型分布有显著性差异(P<0.05);3.A、B组HIF-1α基因G1790A基因型分布不符合Hardy-Weinberg平衡检验(P<0.05),故A、B、C组HIF-1α基因G1790A基因型多态性未作比较。
结论:缺氧缺血性脑病的发病及缺氧缺血性脑损伤所致脑性瘫痪与HIF-1α基因C1772T的单核苷酸多态性有关联。
Objective To study hypoxic-ischemic encephalopathy/ cerebral palsy caused by the hypoxic-ischemic brain disease and HIF-1αgene C1772T/G1790A the relationship between single nucleotide polymorphisms in order to perinatal early intervention to reduce the incidence of hypoxic-ischemic encephalopathy and cerebral palsy caused by the hypoxic-ischemic brain disease. For the prevention and cure of neonatal hypoxic-ischemic encephalopathy find a better theoretical basis
Methods 1. Study is divided into three groups: A group: neonatal hypoxic-ischemic encephalopathy 78 cases; B groups: normal control 100 cases; C group: neonatal hypoxic-ischemic encephalopathy caused 92 cases of children with cerebral palsy ; 2. Peripheral vein blood samples were drawn from the new-borns of each of the groups, from which genomic DNA was extracted respectively according to kit instructions. 3. Application of polymerase chain reaction (PCR) amplification of target gene 346bp, 4. PCR products of digestion and electrophoresis.
Results 1. There was no significant difference in gestational age, birth weight, gender difference and feeding patterns among Group A, B and C (P>0.05). 2. A group of HIF-1αgene 1772CT genotype share more (30.77%),B, C group genotypes of HIF-1α gene 1772CT share less 18%, respectively, 18.57%.A, B, C three groups of HIF-1αgene C1772T genotype distribution was significantly different(P<0.05). HIF-1αgene C1772T / genotype group in the A group (mild, moderate and severe HIE) showed no significant difference(P>0.05). HIF-1αgene C1772T / genotype group in the C group (mild, moderate and severe HIE) showed a significant difference(P<0.05). 3. A, B group of HIF-1αgene G1790A genotypes do not meet Hardy-Weinberg equilibrium test. Therefore, A, B, C group HIF-1αgene G1790A polymorphism does not compare.
Conclusion Hypoxic-ischemic encephalopathy/ cerebral palsy caused by the hypoxic-ischemic brain disease. and HIF-1αgene C1772T single nucleotide polymorphisms are associated.
对象与方法:1.研究分为三组:A组:新生儿缺氧缺血性脑病患儿78例,根据HIE临床表现程度分级,轻度HIE患儿38例、中度HIE患儿26例、重度HIE患儿14例;B组:正常对照100例;C组:新生儿缺氧缺血性脑病所致脑性瘫痪患儿92例,根据既往HIE临床表现程度分级,轻度HIE患儿16例、中度HIE患儿45例、重度HIE患儿31例;2.分别抽取患儿及正常新生儿外周静脉血,参照试剂盒说明分别提取基因组DNA;3.应用聚合酶链反应(PCR)扩增目的基因346bp, 4.PCR产物酶切及电泳。
结果:1.A、B、C三组的孕龄、出生体重、性别差异及喂养方式无显著差异性(P>0.05);2.A组HIF-1α基因1772CT基因型所占较多(30.77%),B、C组HIF-1α基因1772CT基因型所占较少,分别是18%、18.57%,A、B、C三组HIF-1α基因C1772T/基因型分布有显著性差异(P<0.05),A组组内轻度、中度、重度HIE患儿比较HIF-1α基因C1772T/基因型分布无显著性差异(P>0.05),C组轻度、中度、重度HIE患儿比较HIF-1α基因C1772T/基因型分布有显著性差异(P<0.05);3.A、B组HIF-1α基因G1790A基因型分布不符合Hardy-Weinberg平衡检验(P<0.05),故A、B、C组HIF-1α基因G1790A基因型多态性未作比较。
结论:缺氧缺血性脑病的发病及缺氧缺血性脑损伤所致脑性瘫痪与HIF-1α基因C1772T的单核苷酸多态性有关联。
Objective To study hypoxic-ischemic encephalopathy/ cerebral palsy caused by the hypoxic-ischemic brain disease and HIF-1αgene C1772T/G1790A the relationship between single nucleotide polymorphisms in order to perinatal early intervention to reduce the incidence of hypoxic-ischemic encephalopathy and cerebral palsy caused by the hypoxic-ischemic brain disease. For the prevention and cure of neonatal hypoxic-ischemic encephalopathy find a better theoretical basis
Methods 1. Study is divided into three groups: A group: neonatal hypoxic-ischemic encephalopathy 78 cases; B groups: normal control 100 cases; C group: neonatal hypoxic-ischemic encephalopathy caused 92 cases of children with cerebral palsy ; 2. Peripheral vein blood samples were drawn from the new-borns of each of the groups, from which genomic DNA was extracted respectively according to kit instructions. 3. Application of polymerase chain reaction (PCR) amplification of target gene 346bp, 4. PCR products of digestion and electrophoresis.
Results 1. There was no significant difference in gestational age, birth weight, gender difference and feeding patterns among Group A, B and C (P>0.05). 2. A group of HIF-1αgene 1772CT genotype share more (30.77%),B, C group genotypes of HIF-1α gene 1772CT share less 18%, respectively, 18.57%.A, B, C three groups of HIF-1αgene C1772T genotype distribution was significantly different(P<0.05). HIF-1αgene C1772T / genotype group in the A group (mild, moderate and severe HIE) showed no significant difference(P>0.05). HIF-1αgene C1772T / genotype group in the C group (mild, moderate and severe HIE) showed a significant difference(P<0.05). 3. A, B group of HIF-1αgene G1790A genotypes do not meet Hardy-Weinberg equilibrium test. Therefore, A, B, C group HIF-1αgene G1790A polymorphism does not compare.
Conclusion Hypoxic-ischemic encephalopathy/ cerebral palsy caused by the hypoxic-ischemic brain disease. and HIF-1αgene C1772T single nucleotide polymorphisms are associated.
引文
[1]、李松,林庆,刘建蒙,等.中国6省及自治区小儿脑性瘫痪危险因素的研究[J].北京大学学报(医学版),2002,34(3):197-203.
[2]、唐久来,吴德.小儿脑瘫引导式教育疗法[M].人民卫生出版社,2007.16-18
[3]、GiII MB,Perez-Polo JR.Hypoxia ischemia mediated cell death in neonatal rat brain[J].Neuroehem Res,2008,33(12):2379-2389.
[4]、Raju TN.Historical perspectives on the etiology of cerebral palsy[J].Clin Pernatol,2006,33(2):233-50.
[5]、Costeff H.Estimated frequency of genetic and nongenetic causes of congenital idiopathic cerebral palsy in west Sweden.Ann Hum[J].Genet,2004,68(5),515-520.
[6]、Senqenza GL.HIF-1:mediator of physiological andpathophysiologieal responses to hypoxia[J].J Appl Physiol,2000,88(4):1474-1480.
[7]、Wang GL,Semenza GL Purification and characterization of hypoxia inducible factor 1[J].JBiol Chem,1995,270(3):1230-1237.
[8]、刘欣,张长杰编译.小儿脑瘫的研究近况[J].国外医学:物理医学与康复学分册,2004,24(4):145-147
[9]、赵文雅,李纪哲,杨丽梅等.小儿脑瘫的病因与早期诊断及治疗[J].中国妇幼保健,2002,17(8):493
[10]、陆晴友.脑瘫的病因学研究[J].中国康复理论与实践,2003,9(3):191-192
[11]、Schofield CJ,Ratcliffe PJ.Oxygen sensing by HIF hydrox-ylases[J].Nat Rev Mol Cell Biol,2004,5(5):343-354.
[12]、Chandel N S,Budinger GR.The cenular basis for diverse responses to oxygen[J].Free Radic Biol Med,2007,42(2):165-174.
[13]、Ke Q,Costa M.Hypoxia inducible factor-1(-1)[J].Mol Pharmaco1.2006,70(5):1469-1480.
[14]、Semenza G L,Shimoda L A,Prabhakar N R.Regulation of gene expression by-1[J].Novartis Found Symp,2006,272(4):2-8
[15]、Gidday JM.Cerebral preconditioning and ischemic tolerance[J].Nat Rev Neurosci,2006,7(6):437-448.
[16]、Dolt K S,Mishra M K,Karat J,et a1.cDNA cloning gene organization and variant specific expression of H-1 inhighaltitude yak(Bos unniens)[J].Gene,2007,38(6):73-80.
[17]、Fremt T.Valable S,Chazalviel L,et a1.Delayed adtninistration of de femxamfue reduces brain damage and promotes functional recovery after trans ientfocal cerebral iscl1emia in the rat [J].Eur J Neurosci.2006,23:1757-1765.
[18]、Nallka O ,Valasek P,Dvorakova M,et al.Experimental hypoxia and embryonic angiogenesis[J].Developmental Dynamics,2006,235(3):723-733.
[19]、van der Kooij, M.A., Groenendaal, F., Kavelaars, A., Heijnen, C.J., van Bel, F., 2008. Neuroprotective properties and mechanisms of erythropoietin in invitro and in vivo experimentalmodels for hypoxia/ischemia. Brain Res. Rev. 59, 22–33.
[20]、Marti, H.H.,Wenger, R.H., Rivas, L.A., Straumann, U., Digicaylioglu, M., Henn, V., Yonekawa, Y., Bauer, C., Gassmann, M., 1996. Erythropoietin gene expression in human,monkey andmurine brain. Eur. J. Neurosci. 8, 666–676.
[21]、Maiese K,U Fang-qu.Erythropoietin in the brain can the promise to protect be fulfilled [J] Trends Pharmacol Sci,2004,25(11):577-583.
[22]、Arishima,Setoguchi Y,Yamaura,et a1.Preventive effect of erythropoietin on spinal cord cell apoptosis following acute traumatic mjuryin rats[J].Spine,2006,31(21):2432-2438.
[23]、Prass K,Schafff A,Ruscher K,eta1.H ypoxia-induced stroke tolerance in the mouse is mediated by erythropoietin[J].Stroke,2003,34(8):1981-986.
[24]、Shingo T,Sorokan ST,Shimazaki T,et a1.Erythropoietin regulates the invitro and in vivo production of neuronal progenitors by mammalian forebrain neuralstemcells[J].J Neurosci,2001 ,21(24):9733-9743.
[25]、Maiese K,U Fang-qu.Erythropoietin in the brain can the promiseto protect be fulfilled.[J]Trends Pharmacol Sci,2004,25(11):577-583.
[26]、J Jelkmann W.Effects of erythropoietin on brain function[J].Curr Pharm Biotechnol,2005,6(1):65-79.
[27]、Karamysheva, A.F., 2008. Mechanisms of angiogenesis. Biochemistry (Mosc) 73, 751–762.
[28]、Conklin, B.S., Zhao, W., Zhong, D.S., Chen, C., 2002. Nicotine and cotinine up-regulate vascular endothelial growth factor expression in endothelial cells. Am. J. Pathol. 160, 413–418.
[29]、Feng, Y., Rhodes, P.G., Bhatt, A.J., 2008. Neuroprotective effects of vascular endothelial growth factor following hypoxic ischemic brain injury in neonatal rats.Pediatr. Res. 64, 370–374.
[30]、Matsuda T,Abe T.Hypoxia inducable factor-1 dDNA induced angiogenes is in a rat cerebral ischemia modelI J.Neurol Res,2005,27(5):503-508.
[31]、Jin KL,Xiao OM,Nagayama T,et a1.Induction of vascular endothelial growth factor and hypoxia-inducible factor-la by global ischemia in rat brain[J].Neuro-science,2000,99(3):577-585.
[32]、Mu D,Jiang X,Sheldon RA,et a1.Regulation of hypoxia-inducible factor 1alpha and induction of vascular endothelial growth factor in a rat neonatal stroke model[J].Neurobiol Di ,2003,14(3):525-534.
[33]、Pichiule P,Agani F,Chavez JC,et a1.HIF-1 alpha and VEGF expression after transient global cerebral ischemia[J].Adv Exp Med Biol,2003,530:611-617.
[34]、Bernaudin M,Nedelec AS,Divoux D,et a1.Normobarie hypoxia induces tolerance to focal permanent cerebral ischema in association with an increased expression of hypoxia-inducible factor-1 and its target genes.erythro poietin and VEGF,in the adult mouse brain[J].J Cereb Blood Flow Metab,2002,22(4):393-403.
[35]、Marti HJ,Bernaudin M,Bellall A,et a1.Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ichemia[J].AmJ Pathol,2000,156(3):965-976.
[36]、Yeh, W.L., Lu, D.Y., Lin, C.J., Liou, H.C., Fu, W.M., 2007. Inhibition of hypoxia-induced increase of blood–brain barrier permeability by YC-1 through the antagonism of HIF-1alpha accumulation and VEGF expression. Mol. Pharmacol. 72, 440–449.
[37]、Sivakumar, V., Lu, J., Ling, E.A., Kaur, C., 2008. Vascular endothelial growthfactor and nitric oxide production in response to hypoxia in the choroid plexus inneonatal brain. Brain Pathol18, 71–85.
[38]、Zhang, Z.G., Zhang, L., Tsang, W., Soltanian-Zadeh, H., Morris, D., Zhang, R., Goussev, A., Powers, C., Yeich, T., Chopp, M., 2002. Correlation of VEGF and angiopoietin expression with disruption of blood–brain barrier and angiogenesis after focal cerebral ischemia. J. Cereb. Blood Flow Metab. 22, 379–392.
[39]、Bergeron M,Yu AY,Solway KE,et a1.Induction of hypoxia-inducible factor-1(HIF-1)and its target genes following focal ischemia in rat brain[J].Eur J Neurosci,1999,11(12):4159-4170.
[40]、Jones NM,Bergeron M.Hypoxia preconditioning induces changes in HIF-1 target genes in neonatal rat brain[J].J Cereb Blood Flow Metab,2001,21(9): 1105-1114.
[41]、Papandreou I,Cairns RA,Fontana L,et a1.HIF-1 mediates adaptation to hypoxia by actively down regulating mitochondrial oxygen consumption[J].Cell Metab,2006,3(3):187-197.
[42]、Chen, D., Li, M., Luo, J., Gu, W., 2003. Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function. J. Biol. Chem. 278, 13595–13598.
[43]、48、Vogelstein, B., Lane, D., Levine, A.J., 2000. Surfing the p53 network. Nature 408, 307–310.
[44]、Sandau, U.S., Handa, R.J., 2007. Glucocorticoids exacerbate hypoxia-induced expression of the pro-apoptotic gene Bnip3 in the developing cortex. Neuroscience 144, 482–494.
[45]、Chen, G., Ray, R., Dubik, D., Shi, L., Cizeau, J., Bleackley, R.C., Saxena, S., Gietz, R.D., Greenberg, A.H., 1997. The E1B 19K/Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that activates apoptosis. J. Exp. Med. 186, 1975–1983.
[46]、Boyd, J.M., Malstrom, S., Subramanian, T., Venkatesh, L.K.,Schaeper, U., Elangovan, B., D'Sa-Eipper, C., Chinnadurai, G.,1994. Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins. Cell 79, 341–351.
[47]、Jacquemin E,De Vree JM,Cresteil D,et a1.The wide spectrum of muhidrug resistance 3 deficiency : from neonatal cholestasis to cirrhosis of adulthood[J].Gastroen。terology,2001,20(6):1448-1458.
[48]、Halterman,M.W.,Miller, C.C., Federoff, H.J., 1999. Hypoxia-inducible factor-1alpha mediates hypoxia-induced delayed neuronal death that involves p53. J. Neurosci. 19, 6818–6824.
[49]、Suzuki, H., Tomida, A., Tsuruo, T., 2001. Dephosphorylated hypoxia-inducible factor 1alpha as amediator of p53-dependent apoptosis during hypoxia. Oncogene 20, 5779–5788.
[50]、Ropponen A,S u nd R,Riikonen S,et a1.Intrahepatic cholestasis of pregnancy as an indicator of liver and biliary diseases : a population—based study[J].Hepatolog y,2006,43(4):723-728.
[51]、Vallejo M,Briz 0,Serrano MA,et a1.Potential rote of trans-inhibition of the bile salt expofl pump by pmgcsterone metabolites in the etiopathogenesis ofintrahepatic cho-lestasis of pregnancy[J].J Hepatol,2006,44(6):1150-1157.
[52]、Rutherford AE,Prat DS.Cholestasis and cholestatic syn dromes[J].Curr Opin Gas troenterol,2006,22(3):209-214.
[53]、Beuers U,Pusl T.Intrahepatic cholestasis of pregnancya heterogeneous group of pregnancy-related disorders[J].Hepatology,2006,43(4):647-649.
[54]、Jacquemin E,Cresteil D,Manouvrier S,et a1.Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholest asis of pregnancy [J].Lancet,1999,353(9148):210-211.
[55]、Lucena JF,Herrero JI,Quiroga J,et a1.A muhidrug resistance 3 gene mutation causing chotelithiasis,cholestasis of pregnancy,and adulthood biliary cirrhosis[J].Gastro-enterology,2003,124(4):1037-1042.
[56]、Floreani A,Carderi I,Paternoster D,et a1.Intrahe patic cholestasis of pregnancy:three novel MDR3 gene mutations[J].Aliment Pharmacol Ther,2006,23(11):1649-1653.
[57]、Schneider G,Pans TC,Kullak-Ublick G A,et a1 .Linkage between a newsplicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy[J].Hepatology,2007,45(1):150-158
[58]、Greijer, A.E., van der Wall, E., 2004. The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis. J. Clin. Pathol. 57, 1009–1014.
[59]、53、Bianciardi, P., Fantacci,M., Caretti, A., Ronchi, R.,Milano, G.,Morel, S., von Segesser, L., Corno, A., Samaja, M., 2006. Chronic in vivo hypoxia in various organs: hypoxia-inducible factor-1alpha and apoptosis. Biochem. Biophys. Res. Commun. 342, 875–880.
[60]、54、Akakura, N., Kobayashi, M., Horiuchi, I., Suzuki, A.,Wang, J., Chen, J., Niizeki, H., Kawamura, Ki., Hosokawa, M., Asaka, M., 2001. Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res. 61,6548–6554.
[61]、Baranova, O., Miranda, L.F., Pichiule, P., Dragatsis, I., Johnson, R.S., Chavez, J.C., 2007. Neuron-specific inactivation of the hypoxia inducible factor 1 alpha increases brain injury in a mouse model of transient focal cerebral ischemia. J. Neurosci. 27, 6320–6332.
[1]、Bracci R,Perrone S,BuonocoreG..The timing of neonatalbrain damage[J]. Biol. Neonate 2006,90:145–155.
[2]、Northington FJ,Ferriero DM,Martin LJ. Neurodegeneration in the thalamus following neonatal hypoxia–ischemia is programmed cell death[J]. Dev. Neurosci. 2001, 23:186–191.
[3]Kumar A., Mittal R., Khanna HD, Basu, S. Free radical injury and blood–brain barrier permeability in hypoxic–ischemic encephalopathy[J]. Pediatrics 2008,122:722–727.
[4]、Papazisis G., Pourzitaki C, Sardeli C., et a1.Deferoxamine decreases the excitatory amino acid levels and improves the histological outcome in the hippocampus of neonatal rats after hypoxia–ischemia[J]. Pharmacol. Res. 2008, 57: 73–78.
[5]、Pleasure D, Soulika A., Singh SK, et a1.Inflammation in white matter: clinical and pathophysiologica aspects. Ment. Retard[J]. Dev. Disabil. Res. Rev. 2006, 12:141–146.
[6]、Nijboer CH, Heijnen CJ, Groenendaal F, et a1.A. Alternate pathways preserve tumor necrosis factor-alpha production after nuclear factor-kappaB inhibition in neonatal cerebral hypoxia–ischemia[J]. Stroke 2009, 40:3362–3368.
[7]、Goldberg MA., Dunning SP, Bunn HF. Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein[J]. Science 1988 ,242:1412–1415.
[8]、vanden Tweel ER, Kavelaars A, Lombardi M S, Nijboer CH, et a1. Bilateral molecular changes in a neonatal rat model of unilateral hypoxic–ischemic brain damage[J]. Pediatr. Res. 2006,59: 434–439.
[9]、Chen W, Ostrowski RP, Obenaus A, et a1.H. Prodeath or prosurvival: two facets of hypoxia inducible factor-1 in perinatal brain injury[J]. Exp. Neurol. 2009, 216:7–15.
[10]、Lando D, Peet DJ, Whelan DA, et a1.Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch[J]. Science 2002 , 295: 858–861.
[11]、Wiesener MS., Jürgensen JS., Rosenberger C., et a1.Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs[J]. FASEB J. 2002,17:271–273.
[12]、Gu YZ., Moran SM., Hogenesch JB. et a1.Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3alpha[J]. Gene Expr. , 1998,7:205–213.
[13]、Ran R., Xu H., Lu A., et a1.Hypoxia preconditioning in the brain[J]. Dev. Neurosci. 2005, 27: 87–92.
[14]、Wiesener MS., Turley H., Allen W.E., et a1.Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1alpha[J]. Blood , 1998,92:2260–2268.
[15]、Wang GL., Jiang BH., Rue EA., et a1.Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension[J]. Proc. Natl. Acad. Sci. U. S. A. , 1995,92:5510–5514.
[16]、Sharp F R., Bernaudin, M. HIF1 and oxygen sensing in the brain[J]. Nat. Rev., Neurosci. 2004,5:437–448.
[17]、Liu L., Cash TP., Jones RG., et a1.. Hypoxia-induced energy stress regulates mRNA translation and cell growth[J]. Mol. Cell , 2006,21: 521–531.
[18]、Simon, M.C.. Mitochondrial reactive oxygen species are required for hypoxic HIF alpha stabilization[J]. Adv. Exp. Med. Biol. 2006,588: 165–170.
[19]、Minet E., Michel G., Mottet D., et a1.Transduction pathways involved in hypoxia-inducible factor-1 phosphorylation and activation[J]. Free Radic. Biol. Med. 2001,31:847–855.
[20]、O'Rourke JF., Dachs GU., Gleadle JM., et a1.Hypoxia response elements[J]. Oncol. Res. 1997,9:327–332.
[21]、Ratcliffe PJ., O'Rourke JF., Maxwell PH., et a1.Oxygen sensing, hypoxia-inducible factor-1 and the regulation of mammalian gene expression[J]. J. Exp. Biol. 1998, 201: 1153–1162.
[22]、Semenza GL., Jiang BH., Leung SW., et a1. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1[J]. J. Biol. Chem. 1996,271: 32529–32537.
[23]、Vaux EC.,Wood SM., Cockman ME., et a1.Selection of mutant CHO cells with constitutive activation of the HIF system and inactivation of the von Hippel–Lindau tumor suppressor[J]. J. Biol. Chem. 2001, 276:44323–44330.
[24]、Welsh SJ., Koh MY., Powis G.. The hypoxic inducible stress response as a target for cancer drug discovery[J]. Semin. Oncol. 2006, 33:486–497.
[25]、Kalesnykas G., Tuulos T., Uusitalo H., et a1. Neurodegeneration and cellular stress in the retina and optic nerve in rat cerebral ischemia and hypoperfusion models[J]. Neuroscience , 2008,155:937–947.
[26]、Calvert JW., Cahill J., Yamaguchi-Okada M., et a1.Oxygen treatment after experimental hypoxia–ischemia in neonatal rats alters the expression of HIF-1alpha and its downstream target genes[J]. J.Appl. Physiol. ,2006,101:853–865.
[27]、Li L., Qu Y., Li J., et a1.Relationship between HIF-1alpha expression and neuronal apoptosis in neonatal rats with hypoxia–ischemia brain injury[J]. Brain Res. , 2007,1180:133–139.
[28]、Ke Q., Costa M. Hypoxia-inducible factor-1 (HIF-1). Mol. Pharmacol. 2006,70: 1469–1480.
[29]、Iyer NV., Kotch LE., Agani F., et a1.Semenza, G.L. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha[J]. Genes Dev. 1998,12: 149–162.
[30]、Tomita S., Ueno M., Sakamoto M., et a1.Takahama, Y. Defective brain development in mice lacking the Hif-1alpha gene in neural cells[J]. Mol. Cell Biol. 2003,23: 6739–6749.
[31]、Milosevic J., Maisel M., Wegner F., et a1. Lack of hypoxia-inducible factor-1 alpha impairs midbrain neural precursor cells involving vascular endothelial growth factor signaling[J]. J. Neurosci.2007,27: 412–421.
[32]、Rosenberger C., Rosen S., Shina A., et a1. Activation of hypoxia-inducible factors ameliorates hypoxic distal tubular injury in the isolated perfused rat kidney. Nephrol[J]. Dial. Transplant. 2008,23: 3472–3478.
[33]、Schneider C., Krischke G., Keller S., et a1.Short-term effects of pharmacologic HIF stabilization on vasoactive and cytotrophic factors in developing mouse brain[J]. Brain Res. 2009,1280: 43–51.
[34]、vander Kooij M A., Groenendaal F., Kavelaars A., et a1. Neuroprotective properties and mechanisms of erythropoietin in invitro and in vivo experimentalmodels for hypoxia/ischemia[J]. Brain Res. Rev. 2008,59: 22–33.
[35]、Marti HH.,Wenger RH., Rivas LA., et a1. Erythropoietin gene expression in human,monkey andmurine brain[J]. Eur. J. Neurosci. 1996,8: 666–676.
[36]、Nagai A.,Nakagawa E.,Choi HB., et a1.Erythropoietin and erythropoietin receptors in human CNS neurons, astrocytes,microglia, and oligodendrocytes grown in culture[J]. J. Neuropathol. Exp. Neurol. 2001,60, 386–392.
[37]、Marti, H.H. Erythropoietin and the hypoxic brain[J]. J. Exp. Biol. 2004,207: 3233–3242.
[38]、Yeo EJ., Cho YS., Kim M.S., et a1. Contribution of HIF-1alpha or HIF-2alpha to erythropoietin expression: in vivo evidence based on chromatin immunoprecipitation[J]. Ann. Hematol. 2008,87: 11–17
[39]、Mu D., Jiang X., Sheldon RA., et a1.Regulation of hypoxia-inducible factor 1alpha and induction of vascular endothelial growth factor in a rat neonatal strokemodel[J]. Neurobiol. Dis. 2003,14: 524–534.
[40]、Sola A., Rogido M., Lee BH., et a1. Erythropoietin after focal cerebral ischemia activates the Janus kinase-signal transducer and activator of transcription signaling pathway and improves brain injury in postnatal day 7 rats[J]. Pediatr. Res. 2005,57: 481–487.
[41]、Iwai M., Cao G., Yin W., et a1. Erythropoietin promotes neuronal replacement through revascularization and neurogenesis after neonatal hypoxia/ischemia in rats[J]. Stroke , 2007,38: 2795–2803.
[42]、Sharp FR., Ran R., Lu A., et a1.Hypoxic preconditioning protects against ischemic brain injury[J]. NeuroRx , 2004,1: 26–35.
[43]、Stroka DM., Burkhardt T., Desbaillets I., et a1. HIF-1 is expressed in normoxic tissue and displays an organ specific regulation under systemic hypoxia[J]. FASEB J. 2001,15: 2445–2453.
[44]、Mu D., Chang YS., Vexler ZS., et a1.Hypoxia-inducible factor 1alpha and erythropoietin upregulation with deferoxamine salvage after neonatal stroke[J]. Exp. Neurol. 2005,195: 407–415.
[45]、Manalo DJ., Rowan A., Lavoie T., Natarajan L. et a1.Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1[J]. Blood, 2005,105: 659–669.
[46]、Greijer AE., vander Wall E. The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis[J]. J. Clin. Pathol. 2004,57: 1009–1014.
[47]、Chen D., Li M., Luo J., et a1.Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function[J]. J. Biol. Chem. 2003,278: 13595–13598.
[48]、Vogelstein B., Lane D., Levine A.J. Surfing the p53 network[J]. Nature 2000,408: 307–310.
[49]、Sandau US., Handa RJ. Glucocorticoids exacerbate hypoxia-induced expression of the pro-apoptotic gene Bnip3 in the developing cortex[J]. Neuroscience ,2007,144: 482–494.
[50]、Chen G., Ray R., Dubik D., et a1.The E1B 19K/Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that activates apoptosis[J]. J. Exp. Med. 1997,186: 1975–1983.
[51]、Boyd JM., Malstrom S., Subramanian T., et a1.Chinnadurai, G. Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins[J]. Cell,1994,79: 341–351.
[52]、Guo K., Searfoss G., Krolikowski D., et a1.Hypoxia induces the expression of the pro-apoptotic gene BNIP3[J]. Cell Death Differ. 2001,8: 367–376.
[53]、Bianciardi P., Fantacci M., Caretti A., et a1.Chronic in vivo hypoxia in various organs: hypoxia-inducible factor-1alpha and apoptosis[J]. Biochem. Biophys. Res. Commun. 2006,342: 875–880.
[54]、Akakura N., Kobayashi M., Horiuchi I., et a1.Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation[J]. Cancer Res. 2001,61: 6548–6554.
[55]、Halterman MW.,Miller CC., Federoff HJ. Hypoxia-inducible factor-1alpha mediates hypoxia-induced delayed neuronal death that involves p53[J]. J. Neurosci. 1999,19: 6818–6824.
[56]、Suzuki H., Tomida A., Tsuruo T. Dephosphorylated hypoxia-inducible factor 1alpha as amediator of p53-dependent apoptosis during hypoxia[J]. Oncogene ,2001,20: 5779–5788.
[57]、Baranova O., Miranda LF., Pichiule P., et a1.Neuron-specific inactivation of the hypoxia inducible factor 1 alpha increases brain injury in a mouse model of transient focal cerebral ischemia[J]. J. Neurosci. 2007,27: 6320–6332.
[58]、Hossain, M.A. Hypoxic–ischemic injury in neonatal brain: involvement of a novel neuronal molecule in neuronal cell death and potential target forneuroprotection[J]. Int. J. Dev. Neurosci. 2008, 26: 93–101.
[59]、Nakajima W., Ishida A., Lange M.S., et a1.Apoptosis has a prolonged role in the neurodegeneration after hypoxic ischemia in the newborn rat[J]. J. Neurosci. 2000,20: 7994–8004.
[60]、Seta KA.,Yuan Y.,SpicerZ., et a1.The role of calcium in hypoxia-induced signal transduction and gene expression[J]. Cell Calcium. 2004,36: 331–340.
[61]、Zong WX., Thompson CB. Necrotic death as a cell fate[J]. Genes Dev. 2006,20: 1–15.
[62]、Liu J., Liu M.C., Wang KK. Calpain in the CNS: from synaptic function to neurotoxicity[M]. Sci. Signal. 1 re1, 2008.
[63]、Carloni S.,Carnevali A.,Cimino M., et a1.Extended role of necrotic cell death after hypoxia–ischemia-induced neurodegeneration in the neonatal rat. Neurobiol[J]. Dis. 2007,27: 354–361.
[64]、Zhou J.,K?hl R.,Herr B., et a1.Calpain mediates a von Hippel–Lindau protein-independent destruction of hypoxia-inducible factor-1alpha [J]. Mol. Biol. Cell. 2006,17: 1549–1558.
[65]、Hui AS., Bauer AL., Striet JB., et a1.Calcium signaling stimulates translation of HIF-alpha during hypoxia[J]. FASEB J. 2006,20: 466–475.
[66]、Nanduri J.,Wang N., Yuan G., Khan SA., et a1. Intermittent hypoxia degrades HIF-2alpha via calpains resulting in oxidative stress: implications for recurrent apnea-induced morbidities[J]. Proc. Natl. Acad. Sci. U. S. A. 2009,106: 1199–1204.
[67]、Ginouvès nA., Ilc K.,Macías N., et a1. PHDs overactivation during chronic hypoxia“desensitizes”HIFalpha and protects cells from necrosis[J]. Proc. Natl. Acad. Sci. U. S. A. 2008 ,105: 4745–4750.
[68]、Karamysheva AF. Mechanisms of angiogenesis[J]. Biochemistry (Mosc) . 2008,73: 751–762.
[69]、Conklin BS., Zhao W., Zhong DS., et a1.Nicotine and cotinine up-regulate vascular endothelial growth factor expression in endothelial cells[J]. Am. J. Pathol. 2002,160: 413–418.
[70]、Feng Y., Rhodes PG., Bhatt AJ. Neuroprotective effects of vascular endothelial growth factor following hypoxic ischemic brain injury in neonatal rats[J]. Pediatr. Res. 2008, 64: 370–374.
[71]、Saito Y., Uppal A., Byfield G., et a1.Activated NAD(P)H oxidase from supplemental oxygen induces neovascularization independent of VEGF in retinopathy of prematuritymodel[J]. Invest. Ophthalmol. Vis. Sci .2008,49: 1591–1598.
[72]、Forsythe JA., Jiang BH., Iyer NV., et a1. Activation of vascular endothelial growth factor gene transcription by hypoxia inducible factor 1[J]. Mol. Cell Biol. 1996,6:4604–4613.
[73]、Nanka O., Valásek P., DvorákováM., et a1.Experimental hypoxia and embryonic angiogenesis[J].. Dev. Dyn. 2006,235: 723–733.
[74]、Yeh W.L., Lu DY., Lin CJ., et a1. Inhibition of hypoxia-induced increase of blood–brain barrier permeability by YC-1 through the antagonism of HIF-1alpha accumulation and VEGF expression[J]. Mol. Pharmacol. 2007,72:440–449.
[75]、Sivakumar V., Lu J.,LingEA., et a1.Vascular endothelial growth factor and nitric oxide production in response to hypoxia in the choroid plexus in neonatal brain[J]. Brain Pathol. 2008,18:71–85.
[76]、Zhang ZG., Zhang L., Tsang W., et a1. Correlation of VEGF and angiopoietin expression with disruption of blood–brain barrier and angiogenesis after focal cerebral ischemia[J]. J. Cereb. Blood Flow Metab. 2002 ,22: 379–392.
[77]、Muramatsu K., Fukuda A., Togari H., et a1.Vulnerability to cerebral hypoxic–ischemic insult in neonatal but not in adult rats is in parallel with disruption of the blood–brain barrier[J]. Stroke . 1997,28: 2281–2288.
[78]、Bergeron M., Yu AY., Solway KE., et a1. Induction of hypoxia-inducible factor-1 (HIF-1) and its target genes following focal ischaemia in rat brain[J]. Eur. J. Neurosci. 1999 ,11: 4159–4170.
[79]、Marti H J., Bernaudin M., Bellail A., et a1.Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia[J]. Am. J. Pathol. 20001,56: 965–976.
[80]、Schmid-Brunclik N., Bürgi-Taboada C., Antoniou, X., et a1. Astrocyte responses to injury: VEGF simultaneously modulates cell death and proliferation[J]. Am. J. Physiol., Regul. Integr. Comp. Physiol. 2008,295: R864–R873.
[81]、Damert A., Machein M., Breier G.,Fujita, et a1.Up-regulation of vascular endothelial growth factor expression in a rat glioma is conferred by two distinct hypoxia-drivenmechanisms[J]. Cancer Res. 1997, 57: 3860–3864.
[82]、Bernaudin M,Nedelec AS,Divoux D,et a1.Normobaric hypoxia in duces tolerance to focal permanent cerebral ischemia in association wth an increased expression of hypoxia-inducible factor-1 and its target genes,erythro poietin and VEGF,in the adult mouse brain[J].J Cereb Blood Flow Metab,2002,22(4):393-403.
[83]、Aminova LR., Chavez JC.,Lee J., et a1.Prosurvival and prodeath effects of hypoxia-inducible factor-1alpha stabilization in a murine hippocampal cell line[J]. J. Biol. Chem. 2005,280:3996–4003.
[84]、Vangeison G., Carr D,Federoff HJ,et a1.The good, the bad, and the cell type-specific roles of hypoxia inducible factor-1 alpha in neurons and astrocytes[J]. J. Neurosci. 2008 ,28: 1988–1993.
[2]、唐久来,吴德.小儿脑瘫引导式教育疗法[M].人民卫生出版社,2007.16-18
[3]、GiII MB,Perez-Polo JR.Hypoxia ischemia mediated cell death in neonatal rat brain[J].Neuroehem Res,2008,33(12):2379-2389.
[4]、Raju TN.Historical perspectives on the etiology of cerebral palsy[J].Clin Pernatol,2006,33(2):233-50.
[5]、Costeff H.Estimated frequency of genetic and nongenetic causes of congenital idiopathic cerebral palsy in west Sweden.Ann Hum[J].Genet,2004,68(5),515-520.
[6]、Senqenza GL.HIF-1:mediator of physiological andpathophysiologieal responses to hypoxia[J].J Appl Physiol,2000,88(4):1474-1480.
[7]、Wang GL,Semenza GL Purification and characterization of hypoxia inducible factor 1[J].JBiol Chem,1995,270(3):1230-1237.
[8]、刘欣,张长杰编译.小儿脑瘫的研究近况[J].国外医学:物理医学与康复学分册,2004,24(4):145-147
[9]、赵文雅,李纪哲,杨丽梅等.小儿脑瘫的病因与早期诊断及治疗[J].中国妇幼保健,2002,17(8):493
[10]、陆晴友.脑瘫的病因学研究[J].中国康复理论与实践,2003,9(3):191-192
[11]、Schofield CJ,Ratcliffe PJ.Oxygen sensing by HIF hydrox-ylases[J].Nat Rev Mol Cell Biol,2004,5(5):343-354.
[12]、Chandel N S,Budinger GR.The cenular basis for diverse responses to oxygen[J].Free Radic Biol Med,2007,42(2):165-174.
[13]、Ke Q,Costa M.Hypoxia inducible factor-1(-1)[J].Mol Pharmaco1.2006,70(5):1469-1480.
[14]、Semenza G L,Shimoda L A,Prabhakar N R.Regulation of gene expression by-1[J].Novartis Found Symp,2006,272(4):2-8
[15]、Gidday JM.Cerebral preconditioning and ischemic tolerance[J].Nat Rev Neurosci,2006,7(6):437-448.
[16]、Dolt K S,Mishra M K,Karat J,et a1.cDNA cloning gene organization and variant specific expression of H-1 inhighaltitude yak(Bos unniens)[J].Gene,2007,38(6):73-80.
[17]、Fremt T.Valable S,Chazalviel L,et a1.Delayed adtninistration of de femxamfue reduces brain damage and promotes functional recovery after trans ientfocal cerebral iscl1emia in the rat [J].Eur J Neurosci.2006,23:1757-1765.
[18]、Nallka O ,Valasek P,Dvorakova M,et al.Experimental hypoxia and embryonic angiogenesis[J].Developmental Dynamics,2006,235(3):723-733.
[19]、van der Kooij, M.A., Groenendaal, F., Kavelaars, A., Heijnen, C.J., van Bel, F., 2008. Neuroprotective properties and mechanisms of erythropoietin in invitro and in vivo experimentalmodels for hypoxia/ischemia. Brain Res. Rev. 59, 22–33.
[20]、Marti, H.H.,Wenger, R.H., Rivas, L.A., Straumann, U., Digicaylioglu, M., Henn, V., Yonekawa, Y., Bauer, C., Gassmann, M., 1996. Erythropoietin gene expression in human,monkey andmurine brain. Eur. J. Neurosci. 8, 666–676.
[21]、Maiese K,U Fang-qu.Erythropoietin in the brain can the promise to protect be fulfilled [J] Trends Pharmacol Sci,2004,25(11):577-583.
[22]、Arishima,Setoguchi Y,Yamaura,et a1.Preventive effect of erythropoietin on spinal cord cell apoptosis following acute traumatic mjuryin rats[J].Spine,2006,31(21):2432-2438.
[23]、Prass K,Schafff A,Ruscher K,eta1.H ypoxia-induced stroke tolerance in the mouse is mediated by erythropoietin[J].Stroke,2003,34(8):1981-986.
[24]、Shingo T,Sorokan ST,Shimazaki T,et a1.Erythropoietin regulates the invitro and in vivo production of neuronal progenitors by mammalian forebrain neuralstemcells[J].J Neurosci,2001 ,21(24):9733-9743.
[25]、Maiese K,U Fang-qu.Erythropoietin in the brain can the promiseto protect be fulfilled.[J]Trends Pharmacol Sci,2004,25(11):577-583.
[26]、J Jelkmann W.Effects of erythropoietin on brain function[J].Curr Pharm Biotechnol,2005,6(1):65-79.
[27]、Karamysheva, A.F., 2008. Mechanisms of angiogenesis. Biochemistry (Mosc) 73, 751–762.
[28]、Conklin, B.S., Zhao, W., Zhong, D.S., Chen, C., 2002. Nicotine and cotinine up-regulate vascular endothelial growth factor expression in endothelial cells. Am. J. Pathol. 160, 413–418.
[29]、Feng, Y., Rhodes, P.G., Bhatt, A.J., 2008. Neuroprotective effects of vascular endothelial growth factor following hypoxic ischemic brain injury in neonatal rats.Pediatr. Res. 64, 370–374.
[30]、Matsuda T,Abe T.Hypoxia inducable factor-1 dDNA induced angiogenes is in a rat cerebral ischemia modelI J.Neurol Res,2005,27(5):503-508.
[31]、Jin KL,Xiao OM,Nagayama T,et a1.Induction of vascular endothelial growth factor and hypoxia-inducible factor-la by global ischemia in rat brain[J].Neuro-science,2000,99(3):577-585.
[32]、Mu D,Jiang X,Sheldon RA,et a1.Regulation of hypoxia-inducible factor 1alpha and induction of vascular endothelial growth factor in a rat neonatal stroke model[J].Neurobiol Di ,2003,14(3):525-534.
[33]、Pichiule P,Agani F,Chavez JC,et a1.HIF-1 alpha and VEGF expression after transient global cerebral ischemia[J].Adv Exp Med Biol,2003,530:611-617.
[34]、Bernaudin M,Nedelec AS,Divoux D,et a1.Normobarie hypoxia induces tolerance to focal permanent cerebral ischema in association with an increased expression of hypoxia-inducible factor-1 and its target genes.erythro poietin and VEGF,in the adult mouse brain[J].J Cereb Blood Flow Metab,2002,22(4):393-403.
[35]、Marti HJ,Bernaudin M,Bellall A,et a1.Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ichemia[J].AmJ Pathol,2000,156(3):965-976.
[36]、Yeh, W.L., Lu, D.Y., Lin, C.J., Liou, H.C., Fu, W.M., 2007. Inhibition of hypoxia-induced increase of blood–brain barrier permeability by YC-1 through the antagonism of HIF-1alpha accumulation and VEGF expression. Mol. Pharmacol. 72, 440–449.
[37]、Sivakumar, V., Lu, J., Ling, E.A., Kaur, C., 2008. Vascular endothelial growthfactor and nitric oxide production in response to hypoxia in the choroid plexus inneonatal brain. Brain Pathol18, 71–85.
[38]、Zhang, Z.G., Zhang, L., Tsang, W., Soltanian-Zadeh, H., Morris, D., Zhang, R., Goussev, A., Powers, C., Yeich, T., Chopp, M., 2002. Correlation of VEGF and angiopoietin expression with disruption of blood–brain barrier and angiogenesis after focal cerebral ischemia. J. Cereb. Blood Flow Metab. 22, 379–392.
[39]、Bergeron M,Yu AY,Solway KE,et a1.Induction of hypoxia-inducible factor-1(HIF-1)and its target genes following focal ischemia in rat brain[J].Eur J Neurosci,1999,11(12):4159-4170.
[40]、Jones NM,Bergeron M.Hypoxia preconditioning induces changes in HIF-1 target genes in neonatal rat brain[J].J Cereb Blood Flow Metab,2001,21(9): 1105-1114.
[41]、Papandreou I,Cairns RA,Fontana L,et a1.HIF-1 mediates adaptation to hypoxia by actively down regulating mitochondrial oxygen consumption[J].Cell Metab,2006,3(3):187-197.
[42]、Chen, D., Li, M., Luo, J., Gu, W., 2003. Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function. J. Biol. Chem. 278, 13595–13598.
[43]、48、Vogelstein, B., Lane, D., Levine, A.J., 2000. Surfing the p53 network. Nature 408, 307–310.
[44]、Sandau, U.S., Handa, R.J., 2007. Glucocorticoids exacerbate hypoxia-induced expression of the pro-apoptotic gene Bnip3 in the developing cortex. Neuroscience 144, 482–494.
[45]、Chen, G., Ray, R., Dubik, D., Shi, L., Cizeau, J., Bleackley, R.C., Saxena, S., Gietz, R.D., Greenberg, A.H., 1997. The E1B 19K/Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that activates apoptosis. J. Exp. Med. 186, 1975–1983.
[46]、Boyd, J.M., Malstrom, S., Subramanian, T., Venkatesh, L.K.,Schaeper, U., Elangovan, B., D'Sa-Eipper, C., Chinnadurai, G.,1994. Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins. Cell 79, 341–351.
[47]、Jacquemin E,De Vree JM,Cresteil D,et a1.The wide spectrum of muhidrug resistance 3 deficiency : from neonatal cholestasis to cirrhosis of adulthood[J].Gastroen。terology,2001,20(6):1448-1458.
[48]、Halterman,M.W.,Miller, C.C., Federoff, H.J., 1999. Hypoxia-inducible factor-1alpha mediates hypoxia-induced delayed neuronal death that involves p53. J. Neurosci. 19, 6818–6824.
[49]、Suzuki, H., Tomida, A., Tsuruo, T., 2001. Dephosphorylated hypoxia-inducible factor 1alpha as amediator of p53-dependent apoptosis during hypoxia. Oncogene 20, 5779–5788.
[50]、Ropponen A,S u nd R,Riikonen S,et a1.Intrahepatic cholestasis of pregnancy as an indicator of liver and biliary diseases : a population—based study[J].Hepatolog y,2006,43(4):723-728.
[51]、Vallejo M,Briz 0,Serrano MA,et a1.Potential rote of trans-inhibition of the bile salt expofl pump by pmgcsterone metabolites in the etiopathogenesis ofintrahepatic cho-lestasis of pregnancy[J].J Hepatol,2006,44(6):1150-1157.
[52]、Rutherford AE,Prat DS.Cholestasis and cholestatic syn dromes[J].Curr Opin Gas troenterol,2006,22(3):209-214.
[53]、Beuers U,Pusl T.Intrahepatic cholestasis of pregnancya heterogeneous group of pregnancy-related disorders[J].Hepatology,2006,43(4):647-649.
[54]、Jacquemin E,Cresteil D,Manouvrier S,et a1.Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholest asis of pregnancy [J].Lancet,1999,353(9148):210-211.
[55]、Lucena JF,Herrero JI,Quiroga J,et a1.A muhidrug resistance 3 gene mutation causing chotelithiasis,cholestasis of pregnancy,and adulthood biliary cirrhosis[J].Gastro-enterology,2003,124(4):1037-1042.
[56]、Floreani A,Carderi I,Paternoster D,et a1.Intrahe patic cholestasis of pregnancy:three novel MDR3 gene mutations[J].Aliment Pharmacol Ther,2006,23(11):1649-1653.
[57]、Schneider G,Pans TC,Kullak-Ublick G A,et a1 .Linkage between a newsplicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy[J].Hepatology,2007,45(1):150-158
[58]、Greijer, A.E., van der Wall, E., 2004. The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis. J. Clin. Pathol. 57, 1009–1014.
[59]、53、Bianciardi, P., Fantacci,M., Caretti, A., Ronchi, R.,Milano, G.,Morel, S., von Segesser, L., Corno, A., Samaja, M., 2006. Chronic in vivo hypoxia in various organs: hypoxia-inducible factor-1alpha and apoptosis. Biochem. Biophys. Res. Commun. 342, 875–880.
[60]、54、Akakura, N., Kobayashi, M., Horiuchi, I., Suzuki, A.,Wang, J., Chen, J., Niizeki, H., Kawamura, Ki., Hosokawa, M., Asaka, M., 2001. Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res. 61,6548–6554.
[61]、Baranova, O., Miranda, L.F., Pichiule, P., Dragatsis, I., Johnson, R.S., Chavez, J.C., 2007. Neuron-specific inactivation of the hypoxia inducible factor 1 alpha increases brain injury in a mouse model of transient focal cerebral ischemia. J. Neurosci. 27, 6320–6332.
[1]、Bracci R,Perrone S,BuonocoreG..The timing of neonatalbrain damage[J]. Biol. Neonate 2006,90:145–155.
[2]、Northington FJ,Ferriero DM,Martin LJ. Neurodegeneration in the thalamus following neonatal hypoxia–ischemia is programmed cell death[J]. Dev. Neurosci. 2001, 23:186–191.
[3]Kumar A., Mittal R., Khanna HD, Basu, S. Free radical injury and blood–brain barrier permeability in hypoxic–ischemic encephalopathy[J]. Pediatrics 2008,122:722–727.
[4]、Papazisis G., Pourzitaki C, Sardeli C., et a1.Deferoxamine decreases the excitatory amino acid levels and improves the histological outcome in the hippocampus of neonatal rats after hypoxia–ischemia[J]. Pharmacol. Res. 2008, 57: 73–78.
[5]、Pleasure D, Soulika A., Singh SK, et a1.Inflammation in white matter: clinical and pathophysiologica aspects. Ment. Retard[J]. Dev. Disabil. Res. Rev. 2006, 12:141–146.
[6]、Nijboer CH, Heijnen CJ, Groenendaal F, et a1.A. Alternate pathways preserve tumor necrosis factor-alpha production after nuclear factor-kappaB inhibition in neonatal cerebral hypoxia–ischemia[J]. Stroke 2009, 40:3362–3368.
[7]、Goldberg MA., Dunning SP, Bunn HF. Regulation of the erythropoietin gene: evidence that the oxygen sensor is a heme protein[J]. Science 1988 ,242:1412–1415.
[8]、vanden Tweel ER, Kavelaars A, Lombardi M S, Nijboer CH, et a1. Bilateral molecular changes in a neonatal rat model of unilateral hypoxic–ischemic brain damage[J]. Pediatr. Res. 2006,59: 434–439.
[9]、Chen W, Ostrowski RP, Obenaus A, et a1.H. Prodeath or prosurvival: two facets of hypoxia inducible factor-1 in perinatal brain injury[J]. Exp. Neurol. 2009, 216:7–15.
[10]、Lando D, Peet DJ, Whelan DA, et a1.Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch[J]. Science 2002 , 295: 858–861.
[11]、Wiesener MS., Jürgensen JS., Rosenberger C., et a1.Widespread hypoxia-inducible expression of HIF-2alpha in distinct cell populations of different organs[J]. FASEB J. 2002,17:271–273.
[12]、Gu YZ., Moran SM., Hogenesch JB. et a1.Molecular characterization and chromosomal localization of a third alpha-class hypoxia inducible factor subunit, HIF3alpha[J]. Gene Expr. , 1998,7:205–213.
[13]、Ran R., Xu H., Lu A., et a1.Hypoxia preconditioning in the brain[J]. Dev. Neurosci. 2005, 27: 87–92.
[14]、Wiesener MS., Turley H., Allen W.E., et a1.Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1alpha[J]. Blood , 1998,92:2260–2268.
[15]、Wang GL., Jiang BH., Rue EA., et a1.Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension[J]. Proc. Natl. Acad. Sci. U. S. A. , 1995,92:5510–5514.
[16]、Sharp F R., Bernaudin, M. HIF1 and oxygen sensing in the brain[J]. Nat. Rev., Neurosci. 2004,5:437–448.
[17]、Liu L., Cash TP., Jones RG., et a1.. Hypoxia-induced energy stress regulates mRNA translation and cell growth[J]. Mol. Cell , 2006,21: 521–531.
[18]、Simon, M.C.. Mitochondrial reactive oxygen species are required for hypoxic HIF alpha stabilization[J]. Adv. Exp. Med. Biol. 2006,588: 165–170.
[19]、Minet E., Michel G., Mottet D., et a1.Transduction pathways involved in hypoxia-inducible factor-1 phosphorylation and activation[J]. Free Radic. Biol. Med. 2001,31:847–855.
[20]、O'Rourke JF., Dachs GU., Gleadle JM., et a1.Hypoxia response elements[J]. Oncol. Res. 1997,9:327–332.
[21]、Ratcliffe PJ., O'Rourke JF., Maxwell PH., et a1.Oxygen sensing, hypoxia-inducible factor-1 and the regulation of mammalian gene expression[J]. J. Exp. Biol. 1998, 201: 1153–1162.
[22]、Semenza GL., Jiang BH., Leung SW., et a1. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1[J]. J. Biol. Chem. 1996,271: 32529–32537.
[23]、Vaux EC.,Wood SM., Cockman ME., et a1.Selection of mutant CHO cells with constitutive activation of the HIF system and inactivation of the von Hippel–Lindau tumor suppressor[J]. J. Biol. Chem. 2001, 276:44323–44330.
[24]、Welsh SJ., Koh MY., Powis G.. The hypoxic inducible stress response as a target for cancer drug discovery[J]. Semin. Oncol. 2006, 33:486–497.
[25]、Kalesnykas G., Tuulos T., Uusitalo H., et a1. Neurodegeneration and cellular stress in the retina and optic nerve in rat cerebral ischemia and hypoperfusion models[J]. Neuroscience , 2008,155:937–947.
[26]、Calvert JW., Cahill J., Yamaguchi-Okada M., et a1.Oxygen treatment after experimental hypoxia–ischemia in neonatal rats alters the expression of HIF-1alpha and its downstream target genes[J]. J.Appl. Physiol. ,2006,101:853–865.
[27]、Li L., Qu Y., Li J., et a1.Relationship between HIF-1alpha expression and neuronal apoptosis in neonatal rats with hypoxia–ischemia brain injury[J]. Brain Res. , 2007,1180:133–139.
[28]、Ke Q., Costa M. Hypoxia-inducible factor-1 (HIF-1). Mol. Pharmacol. 2006,70: 1469–1480.
[29]、Iyer NV., Kotch LE., Agani F., et a1.Semenza, G.L. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha[J]. Genes Dev. 1998,12: 149–162.
[30]、Tomita S., Ueno M., Sakamoto M., et a1.Takahama, Y. Defective brain development in mice lacking the Hif-1alpha gene in neural cells[J]. Mol. Cell Biol. 2003,23: 6739–6749.
[31]、Milosevic J., Maisel M., Wegner F., et a1. Lack of hypoxia-inducible factor-1 alpha impairs midbrain neural precursor cells involving vascular endothelial growth factor signaling[J]. J. Neurosci.2007,27: 412–421.
[32]、Rosenberger C., Rosen S., Shina A., et a1. Activation of hypoxia-inducible factors ameliorates hypoxic distal tubular injury in the isolated perfused rat kidney. Nephrol[J]. Dial. Transplant. 2008,23: 3472–3478.
[33]、Schneider C., Krischke G., Keller S., et a1.Short-term effects of pharmacologic HIF stabilization on vasoactive and cytotrophic factors in developing mouse brain[J]. Brain Res. 2009,1280: 43–51.
[34]、vander Kooij M A., Groenendaal F., Kavelaars A., et a1. Neuroprotective properties and mechanisms of erythropoietin in invitro and in vivo experimentalmodels for hypoxia/ischemia[J]. Brain Res. Rev. 2008,59: 22–33.
[35]、Marti HH.,Wenger RH., Rivas LA., et a1. Erythropoietin gene expression in human,monkey andmurine brain[J]. Eur. J. Neurosci. 1996,8: 666–676.
[36]、Nagai A.,Nakagawa E.,Choi HB., et a1.Erythropoietin and erythropoietin receptors in human CNS neurons, astrocytes,microglia, and oligodendrocytes grown in culture[J]. J. Neuropathol. Exp. Neurol. 2001,60, 386–392.
[37]、Marti, H.H. Erythropoietin and the hypoxic brain[J]. J. Exp. Biol. 2004,207: 3233–3242.
[38]、Yeo EJ., Cho YS., Kim M.S., et a1. Contribution of HIF-1alpha or HIF-2alpha to erythropoietin expression: in vivo evidence based on chromatin immunoprecipitation[J]. Ann. Hematol. 2008,87: 11–17
[39]、Mu D., Jiang X., Sheldon RA., et a1.Regulation of hypoxia-inducible factor 1alpha and induction of vascular endothelial growth factor in a rat neonatal strokemodel[J]. Neurobiol. Dis. 2003,14: 524–534.
[40]、Sola A., Rogido M., Lee BH., et a1. Erythropoietin after focal cerebral ischemia activates the Janus kinase-signal transducer and activator of transcription signaling pathway and improves brain injury in postnatal day 7 rats[J]. Pediatr. Res. 2005,57: 481–487.
[41]、Iwai M., Cao G., Yin W., et a1. Erythropoietin promotes neuronal replacement through revascularization and neurogenesis after neonatal hypoxia/ischemia in rats[J]. Stroke , 2007,38: 2795–2803.
[42]、Sharp FR., Ran R., Lu A., et a1.Hypoxic preconditioning protects against ischemic brain injury[J]. NeuroRx , 2004,1: 26–35.
[43]、Stroka DM., Burkhardt T., Desbaillets I., et a1. HIF-1 is expressed in normoxic tissue and displays an organ specific regulation under systemic hypoxia[J]. FASEB J. 2001,15: 2445–2453.
[44]、Mu D., Chang YS., Vexler ZS., et a1.Hypoxia-inducible factor 1alpha and erythropoietin upregulation with deferoxamine salvage after neonatal stroke[J]. Exp. Neurol. 2005,195: 407–415.
[45]、Manalo DJ., Rowan A., Lavoie T., Natarajan L. et a1.Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1[J]. Blood, 2005,105: 659–669.
[46]、Greijer AE., vander Wall E. The role of hypoxia inducible factor 1 (HIF-1) in hypoxia induced apoptosis[J]. J. Clin. Pathol. 2004,57: 1009–1014.
[47]、Chen D., Li M., Luo J., et a1.Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function[J]. J. Biol. Chem. 2003,278: 13595–13598.
[48]、Vogelstein B., Lane D., Levine A.J. Surfing the p53 network[J]. Nature 2000,408: 307–310.
[49]、Sandau US., Handa RJ. Glucocorticoids exacerbate hypoxia-induced expression of the pro-apoptotic gene Bnip3 in the developing cortex[J]. Neuroscience ,2007,144: 482–494.
[50]、Chen G., Ray R., Dubik D., et a1.The E1B 19K/Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that activates apoptosis[J]. J. Exp. Med. 1997,186: 1975–1983.
[51]、Boyd JM., Malstrom S., Subramanian T., et a1.Chinnadurai, G. Adenovirus E1B 19 kDa and Bcl-2 proteins interact with a common set of cellular proteins[J]. Cell,1994,79: 341–351.
[52]、Guo K., Searfoss G., Krolikowski D., et a1.Hypoxia induces the expression of the pro-apoptotic gene BNIP3[J]. Cell Death Differ. 2001,8: 367–376.
[53]、Bianciardi P., Fantacci M., Caretti A., et a1.Chronic in vivo hypoxia in various organs: hypoxia-inducible factor-1alpha and apoptosis[J]. Biochem. Biophys. Res. Commun. 2006,342: 875–880.
[54]、Akakura N., Kobayashi M., Horiuchi I., et a1.Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation[J]. Cancer Res. 2001,61: 6548–6554.
[55]、Halterman MW.,Miller CC., Federoff HJ. Hypoxia-inducible factor-1alpha mediates hypoxia-induced delayed neuronal death that involves p53[J]. J. Neurosci. 1999,19: 6818–6824.
[56]、Suzuki H., Tomida A., Tsuruo T. Dephosphorylated hypoxia-inducible factor 1alpha as amediator of p53-dependent apoptosis during hypoxia[J]. Oncogene ,2001,20: 5779–5788.
[57]、Baranova O., Miranda LF., Pichiule P., et a1.Neuron-specific inactivation of the hypoxia inducible factor 1 alpha increases brain injury in a mouse model of transient focal cerebral ischemia[J]. J. Neurosci. 2007,27: 6320–6332.
[58]、Hossain, M.A. Hypoxic–ischemic injury in neonatal brain: involvement of a novel neuronal molecule in neuronal cell death and potential target forneuroprotection[J]. Int. J. Dev. Neurosci. 2008, 26: 93–101.
[59]、Nakajima W., Ishida A., Lange M.S., et a1.Apoptosis has a prolonged role in the neurodegeneration after hypoxic ischemia in the newborn rat[J]. J. Neurosci. 2000,20: 7994–8004.
[60]、Seta KA.,Yuan Y.,SpicerZ., et a1.The role of calcium in hypoxia-induced signal transduction and gene expression[J]. Cell Calcium. 2004,36: 331–340.
[61]、Zong WX., Thompson CB. Necrotic death as a cell fate[J]. Genes Dev. 2006,20: 1–15.
[62]、Liu J., Liu M.C., Wang KK. Calpain in the CNS: from synaptic function to neurotoxicity[M]. Sci. Signal. 1 re1, 2008.
[63]、Carloni S.,Carnevali A.,Cimino M., et a1.Extended role of necrotic cell death after hypoxia–ischemia-induced neurodegeneration in the neonatal rat. Neurobiol[J]. Dis. 2007,27: 354–361.
[64]、Zhou J.,K?hl R.,Herr B., et a1.Calpain mediates a von Hippel–Lindau protein-independent destruction of hypoxia-inducible factor-1alpha [J]. Mol. Biol. Cell. 2006,17: 1549–1558.
[65]、Hui AS., Bauer AL., Striet JB., et a1.Calcium signaling stimulates translation of HIF-alpha during hypoxia[J]. FASEB J. 2006,20: 466–475.
[66]、Nanduri J.,Wang N., Yuan G., Khan SA., et a1. Intermittent hypoxia degrades HIF-2alpha via calpains resulting in oxidative stress: implications for recurrent apnea-induced morbidities[J]. Proc. Natl. Acad. Sci. U. S. A. 2009,106: 1199–1204.
[67]、Ginouvès nA., Ilc K.,Macías N., et a1. PHDs overactivation during chronic hypoxia“desensitizes”HIFalpha and protects cells from necrosis[J]. Proc. Natl. Acad. Sci. U. S. A. 2008 ,105: 4745–4750.
[68]、Karamysheva AF. Mechanisms of angiogenesis[J]. Biochemistry (Mosc) . 2008,73: 751–762.
[69]、Conklin BS., Zhao W., Zhong DS., et a1.Nicotine and cotinine up-regulate vascular endothelial growth factor expression in endothelial cells[J]. Am. J. Pathol. 2002,160: 413–418.
[70]、Feng Y., Rhodes PG., Bhatt AJ. Neuroprotective effects of vascular endothelial growth factor following hypoxic ischemic brain injury in neonatal rats[J]. Pediatr. Res. 2008, 64: 370–374.
[71]、Saito Y., Uppal A., Byfield G., et a1.Activated NAD(P)H oxidase from supplemental oxygen induces neovascularization independent of VEGF in retinopathy of prematuritymodel[J]. Invest. Ophthalmol. Vis. Sci .2008,49: 1591–1598.
[72]、Forsythe JA., Jiang BH., Iyer NV., et a1. Activation of vascular endothelial growth factor gene transcription by hypoxia inducible factor 1[J]. Mol. Cell Biol. 1996,6:4604–4613.
[73]、Nanka O., Valásek P., DvorákováM., et a1.Experimental hypoxia and embryonic angiogenesis[J].. Dev. Dyn. 2006,235: 723–733.
[74]、Yeh W.L., Lu DY., Lin CJ., et a1. Inhibition of hypoxia-induced increase of blood–brain barrier permeability by YC-1 through the antagonism of HIF-1alpha accumulation and VEGF expression[J]. Mol. Pharmacol. 2007,72:440–449.
[75]、Sivakumar V., Lu J.,LingEA., et a1.Vascular endothelial growth factor and nitric oxide production in response to hypoxia in the choroid plexus in neonatal brain[J]. Brain Pathol. 2008,18:71–85.
[76]、Zhang ZG., Zhang L., Tsang W., et a1. Correlation of VEGF and angiopoietin expression with disruption of blood–brain barrier and angiogenesis after focal cerebral ischemia[J]. J. Cereb. Blood Flow Metab. 2002 ,22: 379–392.
[77]、Muramatsu K., Fukuda A., Togari H., et a1.Vulnerability to cerebral hypoxic–ischemic insult in neonatal but not in adult rats is in parallel with disruption of the blood–brain barrier[J]. Stroke . 1997,28: 2281–2288.
[78]、Bergeron M., Yu AY., Solway KE., et a1. Induction of hypoxia-inducible factor-1 (HIF-1) and its target genes following focal ischaemia in rat brain[J]. Eur. J. Neurosci. 1999 ,11: 4159–4170.
[79]、Marti H J., Bernaudin M., Bellail A., et a1.Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia[J]. Am. J. Pathol. 20001,56: 965–976.
[80]、Schmid-Brunclik N., Bürgi-Taboada C., Antoniou, X., et a1. Astrocyte responses to injury: VEGF simultaneously modulates cell death and proliferation[J]. Am. J. Physiol., Regul. Integr. Comp. Physiol. 2008,295: R864–R873.
[81]、Damert A., Machein M., Breier G.,Fujita, et a1.Up-regulation of vascular endothelial growth factor expression in a rat glioma is conferred by two distinct hypoxia-drivenmechanisms[J]. Cancer Res. 1997, 57: 3860–3864.
[82]、Bernaudin M,Nedelec AS,Divoux D,et a1.Normobaric hypoxia in duces tolerance to focal permanent cerebral ischemia in association wth an increased expression of hypoxia-inducible factor-1 and its target genes,erythro poietin and VEGF,in the adult mouse brain[J].J Cereb Blood Flow Metab,2002,22(4):393-403.
[83]、Aminova LR., Chavez JC.,Lee J., et a1.Prosurvival and prodeath effects of hypoxia-inducible factor-1alpha stabilization in a murine hippocampal cell line[J]. J. Biol. Chem. 2005,280:3996–4003.
[84]、Vangeison G., Carr D,Federoff HJ,et a1.The good, the bad, and the cell type-specific roles of hypoxia inducible factor-1 alpha in neurons and astrocytes[J]. J. Neurosci. 2008 ,28: 1988–1993.