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作者：谢娅郑州大学

学位级别：硕士

背景和目的妊娠期高血压疾病是导致孕产妇及围生儿死亡的主要原因之一，病因至今不明。滋养细胞浅着床、胎盘血管重铸障碍致胎盘灌注不足是妊娠期高血压疾病发病的关键环节。缺氧可使滋养细胞浸润过浅，子宫螺旋动脉生理重塑不良，造成... 详细信息

背景和目的妊娠期高血压疾病是导致孕产妇及围生儿死亡的主要原因之一，病因至今不明。滋养细胞浅着床、胎盘血管重铸障碍致胎盘灌注不足是妊娠期高血压疾病发病的关键环节。缺氧可使滋养细胞浸润过浅，子宫螺旋动脉生理重塑不良，造成胎盘缺血缺氧，导致妊娠期高血压疾病的发生。缺氧诱导因子-1（hypoxia-inducible factor 1，HIF-1）对缺氧环境下肿瘤血管生成、细胞氧平衡和能量代谢等的调节起主要作用。bnip3（the Bcl-2 nineteen kilodalton interacting protein 3）是Bcl-2家族的前凋亡因子，据报道bnip3的表达可以被缺氧所诱导，受HIF-1调节，在缺氧组织中过表达。近来还发现，胎盘凋亡和缺氧一样也是妊娠期高血压疾病的发病原因。核因子-κB（nuclear factor-kappaB，NF-κB）是1986年发现的转录因子，包括NF-κB／P65及NF-κB／P50。NF-κB在机体的免疫应答、炎症反应及细胞生长发育、凋亡等多种生理、病理过程中发挥重要作用。目前国内关于bnip3在妊娠期高血压疾病中的作用还未见报道。尽管已知子痫前期患者胎盘凋亡增加，但转录因子NF-κB在此过程中的作用仍存在争论。故本研究通过检测bnip3和缺氧诱导因子-1α（HIF-1α）在妊娠期高血压疾病胎盘中的表达，旨在探讨缺氧因素在妊娠期高血压疾病发病中的作用；同时通过检测胎盘组织中NF-κB／p65和凋亡相关标志物抗体Caspase-3、Bcl-2的表达，探讨滋养细胞凋亡在妊娠期高血压疾病发病中的意义。材料与方法 1．选择选取郑州大学第一附属医院、郑州大学第三附属医院、郑州市妇幼保健院在2005年7月—2006年3月产科住院的孕周相近的正常妊娠妇女及妊娠期高血压疾病患者共80例，20例正常妊娠妇女为对照组，妊娠期高血压组、轻度子痫前期、重度子痫前期各20例，平均年龄分别为（26.85±4.85）岁、（27.96±5.32）岁、（29.98±5.95）岁，分娩孕周分别为（36.95±2.48）周、（36.38±2.94）周、（35.47±3.38）周。两组孕妇的年龄、孕龄、产次比较，差异无显著性（P＞0.05）。 2．免疫组织化学SABC法检测HIF-1、bnip3在正常妊娠妇女和妊娠期高血压病患者胎盘组织中的表达情况。免疫组织化学SP法检测NF-κB／p65、Caspase-3和Bcl-2蛋白在正常妊娠妇女和妊娠期高血压疾病患者胎盘组织中的表达情况。 3．数据资料应用SPSS1300统计软件进行统计处理。采用（Chi-Square Test）χ2检验，相关性分析用Spearman等级相关检验，检验水准：α=0.05。结果 ***-1α在胎盘的合体滋养细胞、血管内皮细胞的胞浆和胞核中可见棕黄色阳性颗粒，以在胞浆中表达为主。HIF-1α在妊娠期高血压疾病胎盘中的表达（阳性率=65％）各组均较正常对照组（阳性率=90％）明显升高：妊娠期高血压组较对照组明显升高（χ2=7.55，P=0.023＜0.01），轻度子痫前期组较对照组明显升高（χ2=13.40，P=0.04＜0.05），重度子痫前期较对照组明显升高（χ2=8.40，P=0.038＜0.05），HIF-1α在妊娠期高血压疾病胎盘中的表达随疾病严重程度逐渐增加：轻度子痫前期组的表达较妊娠期高血压组增加（χ2=13.80，P=0.03＜0.05），子痫前期重度组的表达与轻度子痫前期组增加（χ2=15.00，P=0.02＜0.05）。 2．99％的妊娠期高血压疾病组组胎盘组织的细胞核和细胞浆中均可被检测到bnip3，以胞核表达为主，在合体滋养层都是（++）～（+++），细胞滋养层为（+），血管壁细胞中也可见棕黄色颗粒。bnip3在对照组主要表达在细胞核中。bnip3在妊娠期高血压疾病组（阳性率=98％）胎盘组织细胞质中的表达各组均较正常对照组（阳性率=95％）明显升高：妊娠期高血压组较对照组明显升高（χ2=22.20，P=0.000＜0.01），轻度子痫前期组较对照组明显升高（χ2=14.60，P=0.002＜0.05），重度子痫前期较对照组明显升高（χ2=14.60，P=0.002＜0.05），bnip3在妊娠期高血压疾病胎盘中的表达随疾病严重程度逐渐增加：轻度子痫前期组的表达较妊娠期高血压组增加（χ2=16.40，P=0.03＜0.05），子痫前期重度组的表达与轻度子痫前期组增加（χ2=15.00，P=0.02＜0.05）。 3．对照组BN

关键词：妊娠高血压疾病免疫组化 HIF-1 bnip3 NF-κB Caspase-3 Bcl-2

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Platonin induces autophagy-associated cell death in human leukemia cells

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Autophagy 2009年第2期5卷 173-183页

作者： Chen, Yu-Jen Huang, Wei-Pang Yang, Yuh-Cheng Lin, Chin-Pin Chen, Seu-Hwa Hsu, Ming-Ling Tseng, Yu-Ju Shieh, Hui-Ru Chen, Yu-Yawn Lee, Jie-Jen Department of Radiation Oncology Mackay Memorial Hospital Taipei Taiwan Department of Medical Research Mackay Memorial Hospital Taipei Taiwan Department of Gynecology and Obstetrics Mackay Memorial Hospital Taipei Taiwan Division of General Surgery Department of Surgery Mackay Memorial Hospital Taipei Taiwan Department of Life Science Institute of Zoology National Taiwan University Taipei Taiwan Department of Pharmacology Taipei Medical University Taipei Taiwan Graduate Institute of Sport Coaching Science Chinese Culture University Taipei Taiwan Mackay Medicine Nursing and Management College Taipei Taiwan Department and Graduate School of Physical Education National Taiwan College of Physical Education Taichung Taiwan Graduate Institute of Pharmacology Taipei Medical University Taipei Taiwan Department of Surgery Mackay Memorial Hospital Taipei 104 92 Chung San North Road Taiwan

Platonin is a photosensitizer used for photodynamic therapy. In this study, we tested the effect of platonin on human leukemic cells. Treatment with platonin in the dark markedly reduced cell membrane integrity, and induced significant G₀/G₁ arrest of a panel of human leukemic cell lines, including U937, HL-60, K562, NB4 and THP-1. Development of hypodiploid cells was not evident in these cell lines within 24 h, but was noted in U937, HL-60 and NB4 cells after 24 h. No myeloid differentiation of these cells was noted after five-day treatment. Intriguingly, exposure of monoblastic U937 cells to platonin caused changes characteristic of autophagy, including appearance of cytoplasmic membranous vacuoles and formation of acidic vesicular organelles (AVO) in more than 95% of cells. The platonin-induced autophagy was accompanied by localization of microtubule-associated protein 1 light chain 3 to autophagosomes. Pretreatment with pancaspase inhibitor Z-VAD-fmk abrogated the platonin-induced hypodiploidity, but had no effect on growth inhibition and formation of AVO, indicating a caspase-independent autophagy-associated cell death. Pretreatment of cells with 3-methyladenine attenuated platonin-mediated growth inhibition and formation of AVO. Platonin augmented the expression of bnip3 in both U937 and K562 cells, whereas had an opposite effect on phosphorylation of mTOR downstream molecule p70S6K. Platonin, at the condition inducing autophagy, induced the mitochondrial membrane permeation. These results suggest that the platonin is capable of inhibiting growth as well as inducing cell death, mainly autophagy-associated, in leukemic cells via a mitochondria-mediated and caspase-independent pathway. A markedly less viability inhibition was noted to human monocytes, the normal counterpart of these myeloid leukemic cells. Platonin, other than a photodynamic agent, may offer significant promise as a therapeutic agent against leukemia. ©2009 Landes Bioscienc

关键词： Autophagy bnip3 Caspase Leukemia Platonin

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Upregulation of bnip3 promotes apoptosis of lung cancer cells that were induced by p53

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2006年第2期346卷 501-507页

作者： Yan, Jin Yun, Huang Yang, Yu Jing, Bai Feng, Chen Song-bin, Fu Harbin Med Coll Med Genet Lab Harbin 150086 Peoples R China Biopharmaceut Key Lab Heilongjiang Province Harbin 150086 Peoples R China

It has been shown that p53 induces cell apoptosis and the Bcl-2 family plays key roles in this process. However, the molecular mechanism of p53 apoptotic pathway is still unclear. Here, we show that overexpression of exogenous wild-type p53 induced apoptosis in lung cancer cells and high metastasis potential cells had a faster rate of apoptosis than low metastasis potential cells. The expression of proapoptotic gene bnip3 was increased significantly both in Anip973 and 95D cell lines which have high metastasis ability, but not AGZY83-a or little increased in 95C cell lines which possess low metastasis ability. Overexpression of bnip3 increases apoptotic rate induced by p53 in AGZY83-a cells. Blocking the expression of bnip3 by siRNA in Anip973 cells decreased apoptotic rate mediated by p53. Taken together, these data suggest that high level expression of bnip3 mediated rapid apoptosis that was triggered by p53 in lung cancer cells. (c) 2006 Elsevier Inc. All rights reserved.

关键词： lung cancer apoptosis p53 bnip3

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The pro-cell death Bcl-2 family member, bnip3, is localized to the nucleus of human glial cells: Implications for glioblastoma multiforme tumor cell survival under hypoxia

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INTERNATIONAL JOURNAL OF CANCER 2006年第7期118卷 1660-1669页

作者： Burton, TR Henson, ES Baijal, P Eisenstat, DD Gibson, SB Univ Manitoba Manitoba Inst Cell Biol Winnipeg MB R3E 0V9 Canada Univ Manitoba Dept Biochem & Med Genet Winnipeg MB Canada Univ Manitoba Dept Pediat & Child Hlth Winnipeg MB Canada Univ Manitoba Dept Human Anat & Cell Sci Winnipeg MB Canada

The Bcl-2 nineteen kilodalton interacting protein 3 (bnip3) is a hypoxia-inducible proapoptotic member of the Bcl-2 family that induces cell death by associating with the mitochondria. Under normal conditions, bnip3 is expressed in skeletal muscle and in the brain at low levels. In many human solid tumors, bnip3 is upregulated in hypoxic regions but paradoxically, this bnip3 expression fails to induce cell death. Herein, we have determined that bnip3 is primarily localized to the nucleus of glial cells of the normal human brain, as well as in the malignant glioma cell line U251. Upon exposure of U251 cells to hypoxia, bnip3 expression in the cytoplasm increases and localizes with the mitochondria, contributing to induction of cell death. In contrast, when bnip3 is forcibly over expressed in the nucleus, it fails to induce cell death. Expression of N-terminal bnip3 (lacking the transmembrane and conserved domains) in U251 cells blocks hypoxia-induced cell death acting as a dominant negative protein by binding to wildtype bnip3 and blocking its association with the mitochondria. In glioblastoma multiforme (GBM) tumors, bnip3 expression is increased in hypoxic regions of the tumor and is primarily localized to the nucleus in similar to 80% of tumors. Hence, bnip3 is sequestered in the nucleus within the brain but under hypoxic conditions, bnip3 becomes primarily cytoplasmic, promoting cell death. In GBMs, bnip3 expression is increased but it remains sequestered in the nucleus in hypoxic regions, thereby blocking bnip3's ability to associate with the mitochondria, providing tumor cells with a possible survival advantage. (c) 2005 Wiley-Liss, Inc.

关键词： bnip3 astrocytes glial cells glioblastoma multiforme hypoxia mitochondria cell death nuclear localization

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Expression of the gene encoding the pro-apoptotic bnip3 protein and stimulation of hypoxia-inducible factor-1α (HIF-1α) protein following focal cerebral ischernia in rats

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NEUROCHEMISTRY INTERNATIONAL 2006年第8期48卷 687-695页

作者： Althaus, J. Bernaudin, M. Petit, E. Toutain, J. Touzani, O. Rami, A. Univ Frankfurt Klinikum Inst Mol & Zellulare Anat D-60590 Frankfurt Germany Univ Caen CNRS UMR 6185 F-14074 Caen France

Hypoxia is a common cause of cell death and is implicated in many disease processes including stroke and chronic degenerative disorders. In response to hypoxia, cells express a variety of genes which allow adaptation to altered metabolic demands, decreased oxygen demands, and the removal of irreversibly damaged cells. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates the adaptive response to hypoxia in cells. In this study, we reported an early, time-related, gradual up-regulation of HIF-1 alpha, and a moderate increase in vascular endothelial growth factor (VEGF)- and erythropoietin (Epo)-levels following transient focal ischemia. Moreover, we demonstrated, for the first time a specific localization of the pro-apoptotic regulator bnip3 in striatal and cortical neurons after transient focal ischemia in rats. Prolonged intranuclear bnip3 immunoreactivity was associated with delayed neuronal death. Experiments showed protein increases on Western blots of brain tissue with peaks at 48 h after ischemia. Epo responds to ischemia in an early stage, whereas VEGF and bnip3 accumulate in cells at later times after ischemia. This suggests the possibility that BH3-only proteins might be one of the major downstream effectors of HIF-1 alpha in hypoxic cell death. These findings open the possibility that the hypoxia-regulated pro-apoptotic protein bnip3 enters the nucleus and could interact with other proteins involved in DNA structure, transcription or mRNA splicing after focal brain ischemia. (c) 2006 Elsevier Ltd. All rights reserved.

关键词： HIF focal cerebral ischemia rat bnip3 VEGF Epo apoptosis

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Localization and developmental ontogeny of the pro-apoptotic bnip3 mRNA in the postnatal rat cortex and hippocampus

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BRAIN RESEARCH 2006年第1期1100卷 55-63页

作者： Sandau, Ursula S. Handa, Robert J. Colorado State Univ Dept Biomed Sci Ft Collins CO 80523 USA

Naturally occurring cell death occurs during the first two postnatal weeks in the rat cortex and hippocampus. During this process, apoptosis is initiated by activating or altering expression of pro-apoptotic members of the Bcl-2 family. bnip3 is a pro-apoptotic member of the Bcl-2 family that induces cell death by opening the mitochondrial permeability transition pore. To date, bnip3 expression in the central nervous system has only been examined during hypoxia-mediated apoptosis in the adult rat brain. In this study, we investigated the localization and ontogeny of bnip3 mRNA expression in the postnatal male and female rat brain. bnip3 mRNA was localized by in situ hybridization in the neonatal cortex, hippocampus, habenula and thalamus. Using quantitative real-time RT-PCR, bnip3 mRNA levels were found to be greatest at postnatal day 6.5 in the female anterior and posterior cingulate cortices and hippocampus. bnip3 mRNA expression also increased in the male anterior cingulate cortex at postnatal day 6.5. However, a developmental change in bnip3 levels did not occur in the male posterior cingulate cortex and hippocampus. In the anterior cingulate cortex on postnatal day 6.0 and adulthood, female rats had significantly greater levels of bnip3 mRNA compared to that of males. Altering levels of testosterone in the neonatal rat did not alter the sex differences in bnip3 mRNA levels. The transient increase in bnip3 mRNA expression correlates with naturally occurring cell death in the neonatal rat cortex and hippocampus. Thus, bnip3 may be a mediator of developmental apoptosis in the postnatal rat brain. (c) 2006 Elsevier B.V. All rights reserved.

关键词： bnip3 apoptosis postnatal naturally occurring cell death Bcl-2 brain

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Pivotal role of Bcl-2 family proteins in the regulation of chondrocyte apoptosis

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JOURNAL OF BIOLOGICAL CHEMISTRY 2008年第39期283卷 26499-26508页

作者： Oshima, Yasushi Akiyama, Toru Hikita, Atsuhiko Iwasawa, Mitsuyasu Nagase, Yuichi Nakamura, Masaki Wakeyama, Hidetoshi Kawamura, Naohiro Ikeda, Toshiyuki Chung, Ung-il Hennighausen, Lothar Kawaguchi, Hiroshi Nakamura, Kozo Tanaka, Sakae Univ Tokyo Fac Med Dept Orthopaed Surg Bunkyo Ku Tokyo 1130033 Japan Sagamihara Hosp Natl Hosp Org Clin Res Ctr Dept Pathomech Kanagawa 2288522 Japan Univ Tokyo Ctr Dis Biol & Integrat Med Bunkyo Ku Tokyo 1130033 Japan NIH Lab Genet & Physiol Bethesda MD 20892 USA

During endochondral ossification, chondrocytes undergo hypertrophic differentiation and die by apoptosis. The level of inorganic phosphate (P-i) elevates at the site of cartilage mineralization, and when chondrocytes were treated with P-i, they underwent rapid apoptosis. Gene silencing of the proapoptotic Bcl-2 homology 3-only molecule bnip3 significantly suppressed P-i-induced apoptosis. Conversely, overexpression of Bcl-xL suppressed, and its knockdown promoted, the apoptosis of chondrocytes. bnip3 was associated with Bcl-xL in chondrocytes stimulated with Pi. Bcl-xL was expressed uniformly in the growth plate chondrocytes, whereas bnip3 expression was exclusively localized in the hypertrophic chondrocytes. Finally, we generated chondrocyte-specific bcl-x knock-out mice using the Cre-loxP recombination system, and we provided evidence that the hypertrophic chondrocyte layer was shortened in those mice because of an increased apoptosis of prehypertrophic and hypertrophic chondrocytes, with the mice afflicted with dwarfism as a result. These results suggest the pivotal role of Bcl-2 family members in the regulation of chondrocyte apoptosis.

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Autophagy as a protective response to bnip3-mediated apoptotic signaling in the heart

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AUTOPHAGY 2006年第4期2卷 307-309页

作者： Hamacher-Brady, Anne Brady, Nathan R. Gottlieb, Roberta A. Gustafsson, Asa B. Scripps Res Inst Dept Mol & Expt Med La Jolla CA 92037 USA

bnip3 is a member of the 'BH3-only' Bd-2 subfamily which has been implicated in apoptotic,(1) necrotic(2) and autophagic cell death.(3,4) We recently reported that bnip3 is a key mediator of mitochondrial dysfunction and cell death in the ex vivo heart following ischemia/reperfusion (I/R).(5) Moreover, we found that bnip3 was involved in upregulation of autophagy in I/R and that bnip3-mediated mitochondrial dysfunction correlated with upregulation of autophagy. Using a model of simulated I/R and overexpression of bnip3 in HL-1 cardiac myocytes, we determined that bnip3-mediated upregulation of autophagic activity constituted a protective response against bnip3 death signaling. Here we present additional evidence that enhanced autophagic activity functions as a cytoprotective pathway to oppose ischemia/reperfusion-related apoptosis.

关键词： bnip3 mitochondria mitophagy ischemia/reperfusion cardiac myocyte

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Regulation of bnip3 in normal and cancer cells

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MOLECULES AND CELLS 2006年第1期21卷 1-6页

作者： Lee, H Paik, SG Chungnam Natl Univ Sch Biosci & Biotechnol Dept Biol Taejon 305764 South Korea Chungnam Natl Univ Inst Biotechnol Taejon 305764 South Korea

Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (bnip3) is a mitochondrial pro-apoptotic protein that has a single Bcl-2 homology 3 (BH3) domain and a COOH-terminal transmembrane (TM) domain. Although it belongs to the Bcl-2 family and can hetero-dimerize with Bcl-2, its pro-apoptotic activity is distinct from those of other members of the Bcl-2 family. For example, cell death mediated by bnip3 is independent of caspases and shows several characteristics of necrosis. Furthermore, the TM domain, but not the BH3 domain, is required for dimerization, mitochondrial targeting and pro-apoptotic activity. bnip3 plays an important role in hypoxia-induced death of normal and malignant cells. Its expression is markedly increased in the hypoxic regions of some solid tumors and appears to be regulated by hypoxia-inducible factor (HIF), which binds to a site on the bnip3 promoter. Silencing, followed by methylation, of the bnip3 gene occurs in a significant proportion of cancer cases, especially in pancreatic cancers. bnip3 also has a role in the death of cardiac myocytes in ischemia. Further studies of bnip3 should provide insight into hypoxic cell death and may contribute to improved treatment of cancers and cardiovascular diseases.

关键词： apoptosis Bcl-2 BH3 bnip3 hypoxia

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Molecular regulation of autophagy and apoptosis during ischemic and non-ischemic cardiomyopathy

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AUTOPHAGY 2008年第4期4卷 427-434页

作者： Shaw, James Kirshenbaum, Lorrie A. Univ Manitoba Inst Cardiovasc Sci Res CtrDept Physiol St Boniface Gen HospFac Med Winnipeg MB R2H 2A6 Canada Univ Manitoba Fac Med Dept Pharmacol & Therapeut Winnipeg MB R3E 0W3 Canada

A significant understanding of the genetic signaling pathways governing the extrinsic and intrinsic apoptotic pathways has been established. In recent years, the role of apoptosis in the heart during ischemic and non-ischemic cardiomyopathies has been under investigation and reported to contribute to ventricular remodeling and heart failure. Autophagy has been recently characterized as an essential cellular process in the heart, but whether autophagy functions as a pro-death or pro-survival program during disease conditions is still not completely understood. The mitochondrial death protein bnip3 has been implicated in both apoptosis and autophagy, and its role in both processes is also discussed.

关键词： apoptosis autophagy ventricular myocytes ischemia/reperfusion hypoxia bnip3 beclin-1

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