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131.
Differential expression of VEGF isoforms and receptors in knee joint menisci under systemic hypoxia 总被引:3,自引:0,他引:3
Hofstaetter JG Saad FA Samuel RE Wunderlich L Choi YH Glimcher MJ 《Biochemical and biophysical research communications》2004,324(2):667-672
Vascular endothelial growth factor (VEGF) gene gives rise to several distinct isoforms of VEGF, which differ in their expression patterns as well as their biochemical and biological properties. We examined the expression levels of VEGF isoforms and their receptors in the medial and lateral meniscus of rabbits under normal physiologic conditions as well their expression levels after 8 and 24 h of systemic normobaric hypoxia (13%). VEGF121 is the most abundant VEGF isoform in the medial and lateral meniscus, followed by VEGF165, VEGF189, and VEGF183. While the soluble VEGF121 and VEGF165 are only upregulated at 8 h of hypoxia, the membrane-bound VEGF183 and VEGF189 are further increased at 24 h. VEGFR-2 is expressed at a much higher level than VEGFR-1 under normal conditions, and both receptors are upregulated under hypoxia. Differential expression levels under normoxia as well as a differential response to hypoxia may indicate different functions of VEGF isoforms in the meniscus. 相似文献
132.
Ferrochelatase (FECH), the last enzyme of the heme biosynthetic pathway, catalyzes the insertion of iron into protoporphyrin to form heme. This pathway provides heme for hemoglobin and other essential hemoproteins. The regulatory role of oxygen in the pathway has not been clearly established. In this study, we examined whether FECH gene expression is upregulated during hypoxia by a mechanism which involves the hypoxia-inducible factor 1 (HIF-1). Two HIF-1 binding motifs were identified within the -150 bp FECH minimal promoter sequence. Exposure of HEL, K562, and Hep-G2 cells to hypoxia for 18 hours resulted in a significant increase in FECH mRNA expression (p < 0.05). Hypoxia also transactivated the minimal promoter for the FECH gene in the cells. Transient co-expression of wild-type HIF-1alpha or a dominant negative HIF-1alpha with the FECH minimal promoter luciferase construct stimulated or blocked FECH promoter activity, respectively. Expression of the von Hippel-Lindau (VHL) tumor suppressor factor blocked the expression of both FECH mRNA and HIF-1alpha protein during normoxic culture of renal carcinoma cell line (RCC4). The results suggest that the FECH gene is a target for HIF-1 during hypoxia. 相似文献
133.
目的:研究应用缺氧对体外培养的大鼠神经干细胞增殖的影响。方法:将细胞分为4小时缺氧组、12小时缺氧组、促红细胞生成素(EPO)中和抗体组、IgG组以及对照组.测定大鼠神经干细胞经缺氧培养后的各组细胞克隆形成率以及EPO的表达变化。结果:单细胞培养条件下,与对照组相比,4小时缺氧组和IgG组克隆形成率明显增高;中和抗体组无明显变化;12小时组克隆形成率降低。但无统计学意义。缺氧4小时后,EPO蛋白在预处理后即刻出现表迭,4h达高峰,8h仍有部分表达。结论:短时间缺氧可以促进神经干细胞增殖.长时间缺氧则作用相反。缺氧对NSCs增殖作用的影响可能是由EPO介导产生。 相似文献
134.
目的应用缺氧动物模型比较纯氧环境(pure oxygen environment,POE,100%氧)与空气环境(roomair environment,RAE,21%氧)复苏对新生大鼠缺氧性大脑皮质神经元超微结构的影响。方法7日龄20只SD(Sprague Dawley)乳鼠建立缺氧2.5 h模型后,分为纯氧环境组(POE)和空气环境组(RAE),每组再根据复氧后时间点分为2个亚组,即24 h组和72 h组,每亚组5只。按时间点取各组乳鼠大脑半球右侧额顶皮质行电镜样品制备,透射电镜观察。结果复氧各组均可见神经元、神经毡和细胞间隙水肿。RAE 24 h组神经元核膜结构不清,细胞器减少,线粒体肿胀、空泡化、嵴断裂;粗面内质网扩张,常呈空泡状,核糖体减少;高尔基复合体囊泡扩张;溶酶体较多。RAE 72 h组细胞器改变同前,但类似凋亡的细胞核较多,坏死细胞亦较其他组多见。POE 24 h组病变较RAE 24 h组轻。POE 72 h组细胞内线粒体及粗面内质网较丰富,病变亦比RAE 72 h组轻。结论POE复苏较RAE复苏可更能缓解缺氧致神经元超微结构的损伤、减少细胞凋亡及减轻脑水肿。提示,纯氧环境对缺氧复苏后大脑皮质神经元有一定的保护作用,并表明本动物模型适合缺氧新生大鼠大脑皮质神经元研究。 相似文献
135.
Rakhee S. Gupte Dhawjbahadur K. Rawat Sukrutha Chettimada Donna L. Cioffi Michael S. Wolin William T. Gerthoffer Ivan F. McMurtry Sachin A. Gupte 《The Journal of biological chemistry》2010,285(25):19561-19571
Hypoxic pulmonary vasoconstriction (HPV) is a physiological response to a decrease in airway O2 tension, but the underlying mechanism is incompletely understood. We studied the contribution of glucose-6-phosphate dehydrogenase (Glc-6-PD), an important regulator of NADPH redox and production of reactive oxygen species, to the development of HPV. We found that hypoxia (95% N2, 5% CO2) increased contraction of bovine pulmonary artery (PA) precontracted with KCl or serotonin. Depletion of extracellular glucose reduced NADPH, NADH, and HPV, substantiating the idea that glucose metabolism and Glc-6-PD play roles in the response of PA to hypoxia. Our data also show that inhibition of glycolysis and mitochondrial respiration (indicated by an increase in NAD+ and decrease in the ATP-to-ADP ratio) by hypoxia, or by inhibitors of pyruvate dehydrogenase or electron transport chain complexes I or III, increased generation of reactive oxygen species, which in turn activated Glc-6-PD. Inhibition of Glc-6-PD decreased Ca2+ sensitivity to the myofilaments and diminished Ca2+-independent and -dependent myosin light chain phosphorylation otherwise increased by hypoxia. Silencing Glc-6-PD expression in PA using a targeted small interfering RNA abolished HPV and decreased extracellular Ca2+-dependent PA contraction increased by hypoxia. Similarly, Glc-6-PD expression and activity were significantly reduced in lungs from Glc-6-PDmut(−/−) mice, and there was a corresponding reduction in HPV. Finally, regression analysis relating Glc-6-PD activity and the NADPH-to-NADP+ ratio to the HPV response clearly indicated a positive linear relationship between Glc-6-PD activity and HPV. Based on these findings, we propose that Glc-6-PD and NADPH redox are crucially involved in the mechanism of HPV and, in turn, may play a key role in increasing pulmonary arterial pressure, which is involved in the development of pulmonary hypertension. 相似文献
136.
137.
C. Jaco Klok Alexander Kaiser John R.B. Lighton Jon F. Harrison 《Journal of insect physiology》2010,56(5):461-469
In Drosophila melanogaster and other insects, increases in atmospheric oxygen partial pressure (aPO2) tend to increase adult body size and decrease tracheal diameters and tracheolar proliferation. If changes in tracheal morphology allow for functional compensation for aPO2, we would predict that higher aPO2 would be associated with higher critical PO2 values (CritPO2) and lower maximal tracheal conductances (Gmax). We measured CritPO2 and Gmax for adult and larval vinegar flies reared for 7-9 generations in 10, 21 or 40 kPa O2. The CritPO2, CO2 emission rates and Gmax values were generally independent of the rearing PO2 these flies had experienced, suggesting that minimal functional changes in tracheal capacities occurred in response to rearing PO2. Larvae were able to continue activity during 20 min of anoxia. The lack of multigenerational rearing PO2 effects on tracheal function suggests that the functional compensation at the whole-body level due to tracheal morphological changes in response to aPO2 may be minimal; alternatively the benefits of such compensation may occur in specific tissues or during processes not assessed by these methods. In larvae, the CritPO2 and the capacity for movement in anoxia suggest adaptations for life in hypoxic organic matter. 相似文献
138.
Koichi Inoue Deborah Branigan Zhi-Gang Xiong 《The Journal of biological chemistry》2010,285(10):7430-7439
Transient receptor potential melastatin 7 (TRPM7) channels are novel Ca2+-permeable non-selective cation channels ubiquitously expressed. Activation of TRPM7 channels has been shown to be involved in cellular Mg2+ homeostasis, diseases caused by abnormal magnesium absorption, and in Ca2+-mediated neuronal injury under ischemic conditions. Here we show strong evidence suggesting that TRPM7 channels also play an important role in cellular Zn2+ homeostasis and in Zn2+-mediated neuronal injury. Using a combination of fluorescent Zn2+ imaging, small interfering RNA, pharmacological analysis, and cell injury assays, we show that activation of TRPM7 channels augmented Zn2+-induced injury of cultured mouse cortical neurons. The Zn2+-mediated neurotoxicity was inhibited by nonspecific TRPM7 blockers Gd3+ or 2-aminoethoxydiphenyl borate, and by knockdown of TRPM7 channels with small interfering RNA. In addition, Zn2+-mediated neuronal injury under oxygen-glucose deprivation conditions was also diminished by silencing TRPM7. Furthermore, we show that overexpression of TRPM7 channels in HEK293 cells increased intracellular Zn2+ accumulation and Zn2+-induced cell injury, while silencing TRPM7 by small interfering RNA attenuated the Zn2+-mediated cell toxicity. Thus, TRPM7 channels may represent a novel target for neurological disorders where Zn2+ toxicity plays an important role. 相似文献
139.
Katarzyna A. Dudek Jér?me E. Lafont Aida Martinez-Sanchez Christopher L. Murphy 《The Journal of biological chemistry》2010,285(32):24381-24387
miRNAs have been shown to be essential for normal cartilage development in the mouse. However, the role of specific miRNAs in cartilage function is unknown. Using rarely available healthy human chondrocytes (obtained from 8 to 50 year old patients), we detected a most highly abundant primary miRNA H19, whose expression was heavily dependent on cartilage master regulator SOX9. Across a range of murine tissues, expression of both H19- and H19-derived miR-675 mirrored that of cartilage-specific SOX9. miR-675 was shown to up-regulate the essential cartilage matrix component COL2A1, and overexpression of miR-675 rescued COL2A1 levels in H19- or SOX9-depleted cells. We thus provide evidence that SOX9 positively regulates COL2A1 in human articular chondrocytes via a previously unreported miR-675-dependent mechanism. This represents a novel pathway regulating cartilage matrix production and identifies miR-675 as a promising new target for cartilage repair. 相似文献
140.
Sabine Vogel Marieke Wottawa Katja Farhat Anke Zieseniss Moritz Schnelle Sinja Le-Huu Melanie von Ahlen Cordula Malz Gieri Camenisch D?rthe M. Katschinski 《The Journal of biological chemistry》2010,285(44):33756-33763
Cells are responding to hypoxia via prolyl-4-hydroxylase domain (PHD) enzymes, which are responsible for oxygen-dependent hydroxylation of the hypoxia-inducible factor (HIF)-1α subunit. To gain further insight into PHD function, we generated knockdown cell models for the PHD2 isoform, which is the main isoform regulating HIF-1α hydroxylation and thus stability in normoxia. Induction of a PHD2 knockdown in tetracycline-inducible HeLa PHD2 knockdown cells resulted in increased F-actin formation as detected by phalloidin staining. A similar effect could be observed in the stably transfected PHD2 knockdown cell clones 1B6 and 3B7. F-actin is at least in part responsible for shaping cell morphology as well as regulating cell migration. Cell migration was impaired significantly as a consequence of PHD2 knockdown in a scratch assay. Mechanistically, PHD2 knockdown resulted in activation of the RhoA (Ras homolog gene family member A)/Rho-associated kinase pathway with subsequent phosphorylation of cofilin. Because cofilin phosphorylation impairs its actin-severing function, this may explain the F-actin phenotype, thereby providing a functional link between PHD2-dependent signaling and cell motility. 相似文献