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bnip3 as a Dual Regulator of Mitochondrial Turnover and Cell Death in the Myocardium

PEDIATRIC CARDIOLOGY 2011年第3期32卷 267-274页

作者： Gustafsson, Asa B. Univ Calif San Diego Skaggs Sch Pharm & Pharmaceut Sci La Jolla CA 92093 USA

The Bcl-2 adenovirus E1B 19 kDa-interacting protein 3 (bnip3) is a pro-apoptotic BH3-only protein associated with the pathogenesis of many diseases, including cancer and cardiovascular disease. Studies over the past decade have provided insight into how bnip3 induces mitochondrial dysfunction and subsequent cell death in cells. More recently, bnip3 was identified as a potent inducer of autophagy in cells. However, the functional role of bnip3-mediated autophagy has been difficult to define and remains controversial. New evidence has emerged suggesting that bnip3 is an important regulator of mitochondrial turnover via autophagy in the myocardium. Also, studies suggest that the induction of bnip3-dependent mitochondrial autophagy is a separately activated process independent of Bax/Bak and the mitochondrial permeability transition pore (mPTP). This review discusses the current understanding of the functional role that bnip3 plays in the myocardium. Recent studies suggest that bnip3 might have a dual function in the myocardium, where it regulates both mitochondrial turnover via autophagy and cell death and that these are two separate processes activated by bnip3.

关键词： Apoptosis Autophagy Bcl-2 family bnip3 Mitochondria Necrosis

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兔退变椎间盘中bnip3的免疫组织化学研究

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局解手术学杂志 2012年第1期21卷 3-5页

作者：刘杰彭娜王建解放军93197部队第三军医大学新桥医院骨科第三军医大学新桥医院手术室

目的探讨兔退变椎间盘中bnip3蛋白的表达情况。方法建立兔椎间盘穿刺退变模型,分别培养2、4、8周后对目的椎间盘进行组织HE染色、番红O染色及bnip3免疫组织化学染色,与正常椎间盘随机对照,检测椎间盘退变程度及bnip3蛋白表达情况。结果... 详细信息

目的探讨兔退变椎间盘中bnip3蛋白的表达情况。方法建立兔椎间盘穿刺退变模型,分别培养2、4、8周后对目的椎间盘进行组织HE染色、番红O染色及bnip3免疫组织化学染色,与正常椎间盘随机对照,检测椎间盘退变程度及bnip3蛋白表达情况。结果成功建立兔椎间盘退变模型,随椎间盘退变程度加重,bnip3蛋白在中央髓核组织中的阳性表达逐渐增强。结论兔椎间盘退变过程中,bnip3蛋白表达增强诱导髓核细胞死亡增加。

关键词：椎间盘退变 bnip3 免疫组织化学

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Intracellular ascorbate enhances hypoxia-inducible factor (HIF)-hydroxylase activity and preferentially suppresses the HIF-1 transcriptional response

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FREE RADICAL BIOLOGY AND MEDICINE 2014年 69卷 308-317页

作者： Kuiper, Caroline Dachs, Gabi U. Currie, Margaret J. Vissers, Margreet C. M. Univ Otago Ctr Free Rad Res Dept Pathol & Biomed Sci Christchurch 8140 New Zealand Univ Otago Mackenzie Canc Res Grp Dept Pathol & Biomed Sci Christchurch 8140 New Zealand

Hypoxia-inducible factor (HIF)-1 drives the transcription of hundreds of genes to support cell survival under conditions of microenvironmental and metabolic stress. HIF-1 is downregulated by iron-containing 2-oxoglutarate-dependent enzymes that require ascorbate as a cofactor. The HIP hydroxylases control both protein stability and the formation of an active transcription complex and, consequently, ascorbate could affect HIF-1 alpha stabilization and/or gene expression, but the relative effect of ascorbate on these separate processes has not been well characterized. In this study we examined the effects of known intracellular ascorbate concentrations on both processes in response to various means of hydroxylase inhibition, including CoCl2, NiCl2, desferrioxamine, dimethyloxalylglycine, and hypoxia. Ascorbate inhibited HIF-1 activity most dramatically with all mechanisms of iron competition. In addition, HIF-1-dependent gene expression was effectively prevented by ascorbate and was inhibited even under conditions that allowed HIF-1 a protein stabilization. This suggests that (1) ascorbate acts primarily to stabilize and reduce the iron atom in the hydroxylase active site and (2) the asparagine hydroxylase controlling HIF-1 transcriptional activity is particularly susceptible to fluctuations in intracellular ascorbate. These findings suggest that ascorbate plays a significant role in supporting HIF-hydroxylase function and that it could thereby modulate the cell survival response. (C) 2014 Elsevier Inc. All rights reserved.

关键词： Ascorbate Hypoxia-inducible factor-1 Cancer Hydroxylase Bcl-2/adenovirus E1B 19-kDa interacting protein 3 bnip3 Vascular endothelial cell growth factor Free radicals

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Autophagy and mitophagy in the myocardium: therapeutic potential and concerns

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BRITISH JOURNAL OF PHARMACOLOGY 2014年第8期171卷 1907-1916页

作者： Jimenez, Rebecca E. Kubli, Dieter A. Gustafsson, Asa B. Univ Calif San Diego Sch Med Dept Pharmacol La Jolla CA 92093 USA

The autophagic-lysosomal degradation pathway is critical for cardiac homeostasis, and defects in this pathway are associated with development of cardiomyopathy. Autophagy is responsible for the normal turnover of organelles and long-lived proteins. Autophagy is also rapidly up-regulated in response to stress, where it rapidly clears dysfunctional organelles and cytotoxic protein aggregates in the cell. Autophagy is also important in clearing dysfunctional mitochondria before they can cause harm to the cell. This quality control mechanism is particularly important in cardiac myocytes, which contain a very high volume of mitochondria. The degradation of proteins and organelles also generates free fatty acids and amino acids, which help maintain energy levels in myocytes during stress conditions. Increases in autophagy have been observed in various cardiovascular diseases, but a major question that remains to be answered is whether enhanced autophagy is an adaptive or maladaptive response to stress. This review discusses the regulation and role of autophagy in the myocardium under baseline conditions and in various aetiologies of heart disease. It also discusses whether this pathway represents a new therapeutic target to treat or prevent cardiovascular disease and the concerns associated with modulating autophagy. Linked ArticlesThis article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit

关键词： autophagy bnip3 heart mitochondria mitophagy Parkin

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Distinct microRNA expression signatures are associated with melanoma subtypes and are regulated by HIF1A

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PIGMENT CELL & MELANOMA RESEARCH 2014年第5期27卷 777-787页

作者： Hwang, Hun-Way Baxter, Laura L. Loftus, Stacie K. Cronin, Julia C. Trivedi, Niraj S. Borate, Bhavesh Pavan, William J. NHGRI Genet Dis Res Branch Dept Hlth & Human Serv NIH Bethesda MD 20892 USA NHGRI Genome Technol Branch Dept Hlth & Human Serv NIH Bethesda MD 20892 USA

The complex genetic changes underlying metastatic melanoma need to be deciphered to develop new and effective therapeutics. Previously, genome-wide microarray analyses of human melanoma identified two reciprocal gene expression programs, including transcripts regulated by either transforming growth factor, beta 1 (TGF1) pathways, or microphthalmia-associated transcription factor (MITF)/SRY-box containing gene 10 (SOX10) pathways. We extended this knowledge by discovering that melanoma cell lines with these two expression programs exhibit distinctive microRNA (miRNA) expression patterns. We also demonstrated that hypoxia-inducible factor 1 alpha (HIF1A) is increased in TGF1 pathway-expressing melanoma cells and that HIF1A upregulates miR-210, miR-218, miR-224, and miR-452. Reduced expression of these four miRNAs in TGF1 pathway-expressing melanoma cells arrests the cell cycle, while their overexpression in mouse melanoma cells increases the expression of the hypoxic response gene bnip3. Taken together, these data suggest that HIF1A may regulate some of the gene expression and biological behavior of TGF1 pathway-expressing melanoma cells, in part via alterations in these four miRNAs.

关键词： melanoma miRNA hypoxia HIF1 bnip3

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HIF-mediated metabolic switching in bladder outlet obstruction mitigates the relaxing effect of mitochondrial inhibition

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LABORATORY INVESTIGATION 2014年第5期94卷 557-568页

作者： Ekman, Mari Uvelius, Bengt Albinsson, Sebastian Sward, Karl Lund Univ Dept Expt Med Sci Biomed Ctr SE-22184 Lund Sweden Fac Sci Dept Biol Lund Sweden Lund Univ Dept Urol SE-22184 Lund Sweden

Prior work demonstrated increased levels of hypoxia-inducible factor-1 alpha (HIF-1 alpha) in the bladder following outlet obstruction, associated with bladder growth and fibrosis. Here we hypothesized that HIF induction in outlet obstruction also switches energetic support of contraction from mitochondrial respiration to glycolysis. To address this hypothesis, we created infravesical outlet obstruction in female Sprague-Dawley rats and examined HIF induction and transcriptional activation. HIF-1 alpha increased after 6 weeks of outlet obstruction as assessed by western blotting and yet transcription factor-binding site analysis indicated HIF activation already at 10 days of obstruction. Accumulation HIF-2 alpha and of Arnt2 proteins were found at 10 days, providing an explanation for the lack of correlation between HIF-1 alpha protein and transcriptional activation. HIF signature targets, including Slc2a1,Tpi1, Eno1 and Ldha increased in obstructed compared with sham-operated bladders. The autophagy markers bnip3 and LC3B-II were also increased at 6 week of obstruction, but electron microscopy did not support mitophagy. Mitochondria were, however, remodeled with increased expression of Cox4 compared with other markers. In keeping with a switch toward glycolytic support of contraction, we found that relaxation by the mitochondrial inhibitor cyanide was reduced in obstructed bladders. This was mimicked by organ culture with the HIF-inducer dimethyloxalylglycine, which also upregulated expression of Ldha. On the basis of these findings, we conclude that HIF activation in outlet obstruction involves mechanisms beyond the accumulation of HIF-1a protein and that it results in a switch of the energetic support of contraction to anaerobic glycolysis. This metabolic adaptation encompasses increased expression of glucose transporters and glycolytic enzymes combined with mitochondrial remodeling. Together, these changes uphold contractility when mitochondrial respiration is l

关键词： bnip3 Edn1 LC3-II P4ha1 Slc2a3

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bnip3在缺氧后少突胶质前体细胞死亡中的作用(英文)

BNIP3在缺氧后少突胶质前体细胞死亡中的作用(英文)

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中国解剖学会2012年年会

作者：李成仁赵玲关腾孔吉明肖岚第三军医大学组织胚胎学教研室加拿大曼尼托巴大学人体解剖与细胞科学系

Oligodendrocyte precursor cells(OPCs) are the majar oligodendrocyte-lineage stage in the white matter of neonatal rat *** studies have shown that OPCs are more senstive to hypoxic-ischemic injury than other cell types,yet the mechanisms are not well ***3 is a member of a unique Bcl-2 subfamily of death-inducing mitochondrial ***,bnip3 is not detectable in brain,expression of endogenous bnip3 is induced in a variety of cells and tissues under hypoxic

关键词：少突胶质前体细胞 bnip3

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Epigenetic Regulation of E2F-1-Dependent bnip3 Transcription and Cell Death by Nuclear Factor-κB and Histone Deacetylase-1

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PEDIATRIC CARDIOLOGY 2011年第3期32卷 263-266页

作者： Gang, Hongying Dhingra, Rimpy Wang, Yan Mughal, Wajihah Gordon, Joseph W. Kirshenbaum, Lorrie A. St Boniface Gen Hosp Res Ctr Dept Pharmacol & Therapeut Fac MedInst Cardiovasc Sci Winnipeg MB R2H 2A6 Canada St Boniface Gen Hosp Res Ctr Dept Physiol Fac MedInst Cardiovasc Sci Winnipeg MB R2H 2A6 Canada

A delicate balance exists between cell growth and cell death. In the context of the adult myocardium, inappropriate or inordinate cell loss through an apoptotic process may profoundly influence cardiac structure, function, or both given the limited and meager ability of the heart for repair after injury. Earlier work by the authors' laboratory identified a close relation between cell cycle factor E2F-1 and hypoxia-inducible factor bnip3 as the key regulator of apoptosis and autophagy in ventricular myocytes. Epigenetic changes by histone-modifying proteins, namely, histone deacetylases (HDACs) influence cell survival by altering the activity of histone core proteins, transcription factors, or both. This report highlights the intricate nature between the cellular factors E2F-1 and nuclear factor-kappa B (NF-kappa B) and the epigenetic regulation of bnip3 gene transcription by HDAC1 for cell survival of ventricular myocytes.

关键词： Apoptosis bnip3 E2F-1 Histone deacetylases Mitochondrion NF-kappa B

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p53与bnip3在胶质母细胞瘤中表达及其相关性

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中华实验外科杂志 2012年第1期29卷 7-7页

作者：沈军赵亮程宏伟冯春国王晓洁程宝春吕波安徽医科大学第一附属医院神经外科合肥230022 安徽医科大学第一附属医院病理科合肥230022 安徽医科大学第四附属医院神经外科

突变型p53不仅在胶质母细胞瘤中表达增加，而且参与了胶质母细胞瘤对化疗药物的耐药机制，且突变型p53可显著抑制bnip3诱导的细胞凋亡，从而导致肿瘤发生。我们通过免疫组织化学检测p53与bcl-2腺病毒E1B19kD结合蛋白（bnip3）在胶质母... 详细信息

突变型p53不仅在胶质母细胞瘤中表达增加，而且参与了胶质母细胞瘤对化疗药物的耐药机制，且突变型p53可显著抑制bnip3诱导的细胞凋亡，从而导致肿瘤发生。我们通过免疫组织化学检测p53与bcl-2腺病毒E1B19kD结合蛋白（bnip3）在胶质母细胞瘤中的表达及其相关性。

关键词：胶质母细胞瘤突变型p53 bnip3 相关性免疫组织化学检测 bcl-2 耐药机制化疗药物

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桔梗皂苷D在体外对人肝癌细胞株HepG2的杀伤作用机制研究

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中国卫生检验杂志 2015年第16期25卷 2754-2757,2760页

作者：徐洁李小兵赖盼建王锦军金华市中心医院浙江金华321000

目的研究桔梗皂苷D在体外对人肝癌细胞株Hep G2的杀伤作用及其机制。方法 MTT法检测桔梗皂苷D对Hep G2细胞增殖的抑制作用,台盼蓝染色法检测桔梗皂苷D对Hep G2细胞死亡的诱导作用。Western blot检测自噬标记蛋白LC3-Ⅱ的表达,并用荧光定... 详细信息

目的研究桔梗皂苷D在体外对人肝癌细胞株Hep G2的杀伤作用及其机制。方法 MTT法检测桔梗皂苷D对Hep G2细胞增殖的抑制作用,台盼蓝染色法检测桔梗皂苷D对Hep G2细胞死亡的诱导作用。Western blot检测自噬标记蛋白LC3-Ⅱ的表达,并用荧光定量PCR法检测自噬相关基因Beclin1的表达。荧光定量PCR法检测Hep G2细胞线粒体膜电位相关蛋白bnip3的表达水平。JC-1染料处理Hep G2细胞,并用流式细胞术检测桔梗皂苷D对线粒体膜电位的影响。结果桔梗皂苷D可显著抑制Hep G2细胞的增殖并杀伤肿瘤细胞。桔梗皂苷D处理后Hep G2细胞的Beclin1水平和LC3-Ⅱ表达显著增高,bnip3表达水平显著增高并诱导其线粒体肿胀,膜电位降低。结论桔梗皂苷D上调bnip3表达,诱导Hep G2细胞发生自噬性死亡。

关键词：桔梗皂苷D 自体吞噬 bnip3 线粒体膜电位

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