低氧诱导因子及其他相关因子与缺血性卒中发病机制的研究进展

低氧是脑血管疾病尤其是缺血性脑卒中过程中一个重要的病理生理因素,是卒中过程中低氧应答时基因表达和恢复内环境平衡的调节中心。低氧诱导因子（HIF-1）对缺血坏死后新生血管的形成和低氧诱导的细胞凋亡过程都是非常关键的因素。调控HIF-1水平可能为缺血性疾病的治疗开辟新的途径。     

HIF-1α及其在视网膜缺氧相关疾病中的研究进展

HIF-1是Semenza GL等1992年发现的一种氧依赖转录激活因子，HIF-1的发现使人们对缺氧缺血状态下机体的各种应答反应机制的研究更加深入。HIF-1是细胞中调节血管生成主要缺氧反应信号蛋白，它能诱导多达70多种转录因子瞳一，包括促红细胞生成素（EPO）、糖酵解酶、诱导型一氧化氮合酶（INOS）和血管内皮生长因子（VEGF）等，这些基因涉及血管发生、红细胞生成、能量代谢、细胞凋亡和增殖等多方面，在细胞和机体的生理病理反应中至关重要。通过纯化证实HIF-1由120000的a亚单位和91～94000的8亚单位组成，其中HIF-1α则为HIF-1所特有，其活性和表达决定HIF-1的生理活性。HIF-1特别是HIF-1α在缺氧相关疾病中的作用越来越受到人们的重视。故本文对HIF-1α及其在视网膜相关疾病中的研究进展作一综述。     

HIF-1α在乳腺癌组织中的表达及其临床意义

乏氧诱导因子-1（HIF-1）是一种随着细胞内氧浓度变化而调节基因表达的转录激活因子，由氧调节亚单位HIF-1α和HIF-1α组成，具有DNA结合活性。其中，HIF-1β在有氧及缺氧状态下均稳定于细胞中，HIF-1α是主要的氧调节亚基，在氧正常时迅速被蛋白酶降解，而在缺氧时半衰期显著延长，可调节多种靶基因如葡萄糖转运因子、VEGF、红细胞生成素等的表达，对维持肿瘤细胞的能量代谢、刺激新生血管生成、促进肿瘤细胞增殖和转移起重要作用。     

缺氧诱导因子及其研究进展

缺氧诱导因子（hypoxia-inducible factor,HIF）是20世纪90年代初,在研究低氧诱导的红细胞生成素（erythropoietin,EPO）基因表达时,从细胞核提取物中发现的参与氧稳态失衡调节的一个核心调节因子.HIF-1在哺乳动物和人体内广泛存在,是低氧活化的转录因子,直接或间接调节着血管生成、细胞增殖与凋亡、能量调节等众多通路.本文就HIF的结构、转录激活系统及其在红系生成、铁代谢稳态、固有免疫以及脂质代谢等方面的研究进展作一综述.     

缺氧诱导因子-1α与糖尿病周围神经病变

糖尿病周围神经病变是糖尿病最常见的慢性并发症之一。缺血、缺氧在糖尿病周围神经病变中起着重要作用,而缺氧可刺激缺氧诱导因子（HIF）-1α表达增强。HIF-1α可增强细胞对低氧的适应能力,对多种细胞具有保护作用,亦可直接抑制神经细胞凋亡以及调节其下游基因血管内皮生长因子、促红细胞生成素等的表达,可能对糖尿病周围神经发挥保护作用。     

HIF-1α和VEGF与肿瘤病理的关系

氧平衡是哺乳动物维持正常生长发育和代谢的基础,是维持细胞生存的重要因素。许多实体肿瘤具有缺氧的微环境,肿瘤细胞对缺氧的自身调节和适应机制主要是通过提高葡萄糖转运、糖酵解及形成血管体系。血管内皮生长因子(VEGF)是肿瘤血管形成过程中最重要的刺激因子,同时又是HIF-1α重要的靶基因,故HIF-1α被认为是肿瘤血管生成环节中的中心启动分子[1]。1 HIF-1α和肿瘤的关系缺氧诱导因子(HIF-1α)是在缺氧的细胞核提取物中发现的一种DNA结合蛋白,是介导细胞对缺氧的微环境进行适应反应的关键性转录调控性因子,是一个异二聚体积bHLH-…     

低氧诱导因子-2对红系造血和铁代谢调控相关蛋白作用的研究进展

低氧诱导因子(HIF)-2是由HIF-2α和HIF-1β组成的异二聚合体.HIF-1通过诱导红细胞生成素基因表达和调节铁代谢等调控红系造血.HIF-2在诱导红细胞生成素基因表达、调节造血微环境以及铁代谢调控相关蛋白等方面发挥着更重要的作用.本文就有关家族性红细胞增多症中的HIF-2α变异、HIF-2诱导红细胞生成素基因表达、HIF-2α基因敲除对造血微环境的影响以及HIF-2对铁代谢相关蛋白调节作用的研究进展作一综述.     

低氧诱导因子-2对红系造血和铁代谢调控相关蛋白作用的研究进展

低氧诱导因子(HIF)-2是由HIF-2α和HIF-1β组成的异二聚合体.HIF-1通过诱导红细胞生成素基因表达和调节铁代谢等调控红系造血.HIF-2在诱导红细胞生成素基因表达、调节造血微环境以及铁代谢调控相关蛋白等方面发挥着更重要的作用.本文就有关家族性红细胞增多症中的HIF-2α变异、HIF-2诱导红细胞生成素基因表达、HIF-2α基因敲除对造血微环境的影响以及HIF-2对铁代谢相关蛋白调节作用的研究进展作一综述.     

缺氧诱导因子-1在风湿性疾病发病过程中的作用

缺氧诱导因子-1(hvpoxia-inducibJefactor-1,HIF-1)是细胞缺氧条件下调控基因表达的主要转录因子之一,Kuwai等[1] 于1991年在研究红细胞生成素(erythropoietin,EPO)基因3'末端含有缺氧诱导的增强子序列的过程中发现.HIF-1作为细胞、组织在低氧环境下产生的一系列适应性反应的核心因子,在促进促EPO、葡萄糖载体、血管源性因子生成及细胞增殖等方面发挥着重要的作用.     

HIF-1α在乳腺癌组织中的表达及其临床意义

乏氧诱导因子-1(HIF-1)是一种随着细胞内氧浓度变化而调节基因表达的转录激活因子,由氧调节亚单位HIF-1α和HIF-1β组成,具有DNA结合活性.其中, HIF-1β在有氧及缺氧状态下均稳定于细胞中, HIF-1α是主要的氧调节亚基,在氧正常时迅速被蛋白酶降解,而在缺氧时半衰期显著延长,可调节多种靶基因如葡萄糖转运因子、VEGF、红细胞生成素等的表达,对维持肿瘤细胞的能量代谢、刺激新生血管生成、促进肿瘤细胞增殖和转移起重要作用.本研究,运用免疫组织化学的方法,检测了乳腺癌组织中HIF-1α的表达情况,现报道如下.     

BH3-only protein Noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor 1alpha

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. Using polymerase chain reaction-based suppression subtractive hybridization to find genes that are differentially expressed in hypoxia, we identified the BH3-only Bcl-2 family protein Noxa. Noxa is a candidate molecule mediating p53-induced apoptosis. We show that Noxa promoter responds directly to hypoxia via hypoxia-inducible factor (HIF)-1alpha. Suppression of Noxa expression by antisense oligonucleotides rescued cells from hypoxia-induced cell death and decreased infarction volumes in an animal model of ischemia. Further, we show that reactive oxygen species and resultant cytochrome c release participate in Noxa-mediated hypoxic cell death. Altogether, our results show that Noxa is induced by HIF-1alpha and mediates hypoxic cell death.     

Fasudil-induced hypoxia-inducible factor-1alpha degradation disrupts a hypoxia-driven vascular endothelial growth factor autocrine mechanism in endothelial cells

Hypoxic response of endothelial cells (EC) is an important component of tumor angiogenesis. Especially, hypoxia-inducible factor-1 (HIF-1)-dependent EC-specific mechanism is an essential component of tumor angiogenesis. Recently, the Rho/Rho-associated kinase (ROCK) signaling has been shown to play a key role in HIF-1alpha induction in renal cell carcinoma and trophoblast. The present study was designed to investigate whether low oxygen conditions might modulate HIF-1alpha expression through the Rho/ROCK signaling in human umbilical vascular ECs (HUVEC). Pull-down assay showed that hypoxia stimulated RhoA activity. Under hypoxic conditions, HUVECs transfected with small interfering RNA of RhoA and ROCK2 exhibited decreased levels of HIF-1alpha protein compared with nontargeted small interfering RNA transfectants, whereas HIF-1alpha mRNA levels were not altered. One of ROCK inhibitors, fasudil, inhibited hypoxia-induced HIF-1alpha expression without altering HIF-1alpha mRNA expression. Furthermore, proteasome inhibitor prevented the effect of fasudil on HIF-1alpha expression, and polyubiquitination was enhanced by fasudil. These results suggested that hypoxia-induced HIF-1alpha expression is through preventing HIF-1alpha degradation by activating the Rho/ROCK signaling in ECs. Furthermore, hypoxia induced both vascular endothelial growth factor (VEGF) and VEGF receptor-2 expression through the Rho/ROCK/HIF-1alpha signaling in HUVECs. Thus, augmented VEGF/VEGF receptor-2 autocrine mechanism stimulated HUVEC migration under hypoxic conditions. In summary, the Rho/ROCK/HIF-1alpha signaling is an essential mechanism for hypoxia-driven, VEGF-mediated autocrine loop in ECs. Therefore, fasudil might have the antimigratory effect against ECs in tumor angiogenesis.     

Hypoxia-inducible factors and hypoxic cell death in tumour physiology

Hypoxic up-regulation of hypoxia-inducible factors (HIFs) during tumourigenesis presents an interesting paradox with respect to their role in tumour growth. Hypoxia-inducible factor 1 (HIF-1) plays a key role in the adaptive response to hypoxia, trans-activating many genes whose protein products are involved in pathways of angiogenesis, glucose metabolism and cell proliferation, thus facilitating tumour progression. However, it is also emerging that up-regulation of HIF-1 trans-activates anti-proliferative and pro-apoptotic genes (such as BNIP3, NIX and IGFBP3). This makes it unclear as to whether HIF-1 up-regulation provides a selective advantage or disadvantage to neoplastic progression under hypoxia. In addition, vagaries in the hypoxic microenvironment of the tumour such as pH changes, presence of reactive oxygen species and energy availability in the form of adenosine triphosphate (ATP), appear to influence the function of HIF-1 and up-regulated pathways and affect susceptibility to undergo hypoxic cell death. It is apparent that hypoxic cancer cells must be able to select against HIF-1 mediated cell death signals in order to survive and progress towards malignancy. Hypoxia-induced HIF-1 may in itself serve to select for increased malignancy by exerting pressure in the form of anti-proliferative signals that must be escaped. Understanding the mechanisms by which HIF-1 induces cell death and the manner in which the tumour cell can overcome such signals, is critical for our understanding of cancer progression and the development of effective therapeutics.     

Intrinsically lower AKT, mammalian target of rapamycin, and hypoxia-inducible factor activity correlates with increased sensitivity to 2-deoxy-D-glucose under hypoxia in lung cancer cell lines

Down-regulation by small interfering RNA or absence of hypoxia-inducible factor (HIF-1alpha) has been shown to lead to increased sensitivity to glycolytic inhibitors in hypoxic tumor cells. In surveying a number of tumor types for differences in intrinsic levels of HIF under hypoxia, we find that the reduction of the upstream pathways of HIF, AKT, and mammalian target of rapamycin (mTOR) correlates with increased toxic effects of 2-deoxy-D-glucose (2-DG) in lung cancer cell lines when treated under hypoxia. Because HIF-1alpha translation is regulated by mTOR, we examined the effects of blocking mTOR under hypoxia with an analogue of rapamycin (CCI-779) in those cell lines that showed increased mTOR and AKT activity and found that HIF-1alpha down-regulation coincided with increased 2-DG killing. CCI-779, however, was ineffective in increasing 2-DG toxicity in cell lines that did not express HIF. These results support the hypothesis that although mTOR inhibition leads to the blockage of numerous downstream targets, CCI-779 increases the toxicity of 2-DG in hypoxic cells through down-regulation of HIF-1alpha. Overall, our findings show that CCI-779 hypersensitizes hypoxic tumor cells to 2-DG and suggests that the intrinsic expression of AKT, mTOR, and HIF in lung cancer, as well as other tumor types, may be important in dictating the decision on how best to use 2-DG alone or in combination with CCI-799 to kill hypoxic tumor cells clinically.     

Impaired wound healing in hypoxic renal tubular cells: roles of hypoxia-inducible factor-1 and glycogen synthase kinase 3β/β-catenin signaling

Wound and subsequent healing are frequently associated with hypoxia. Although hypoxia induces angiogenesis for tissue remodeling during wound healing, it may also affect the healing response of parenchymal cells. Whether and how wound healing is affected by hypoxia in kidney cells and tissues is currently unknown. Here, we used scratch-wound healing and transwell migration models to examine the effect of hypoxia in cultured renal proximal tubular cells (RPTC). Wound healing and migration were significantly slower in hypoxic (1% oxygen) RPTC than normoxic (21% oxygen) cells. Hypoxia-inducible factor-1α (HIF-1α) was induced during scratch-wound healing in normoxia, and the induction was more evident in hypoxia. Nevertheless, HIF-1α-null and wild-type cells healed similarly after scratch wounding. Moreover, activation of HIF-1α with dimethyloxalylglycine in normoxic cells did not suppress wound healing, negating a major role of HIF-1α in wound healing in this model. Scratch-wound healing was also associated with glycogen synthase kinase 3β (GSK3β)/β-catenin signaling, which was further enhanced by hypoxia. Pharmacological inhibition of GSK3β resulted in β-catenin expression, accompanied by the suppression of wound healing and transwell cell migration. Ectopic expression of β-catenin in normoxic cells could also suppress wound healing, mimicking the effect of hypoxia. Conversely, inhibition of β-catenin via dominant negative mutants or short hairpin RNA improved wound healing and transwell migration in hypoxic cells. The results suggest that GSK3β/β-catenin signaling may contribute to defective wound healing in hypoxic renal cells and tissues.