Zhang cuicui, geng deqin
 ( department of neurology of Affiliated Hospital of Xuzhou Medical College, Xuzhou City, Jiangsu Province, 221003 )
(Jiangsu Key Laborotary of Brain Disease Bioinformation, xuzhou city, jiangsu province, 221002)
 [Abstract] at present, there are more than 100 of genes directly regulated by HIF - 1, involved in angiogenesis, erythropoiesis, energy metabolism, cell proliferation and apoptosis, tumor growth and metastasis, and resistance of tumor radiation and chemotherapy and many other aspects. Therefore, it is of great significance to study the role of HIF - 1 and its regulating mechanism.
Key words: HIF - 1; Cerebral ischemic diseases
 
HIF - 1 (Hypoxia inducible factor 1 alpha, HIF - 1) was found by Semenza et al[1]in 1992 while studying gene expression of erythropoietin (EPO) in Hep3B cell line. Later it is found that the factors can regulate various hypoxic reaction gene transcription, involved in hypoxic response signal transduction process, hence named HIF - 1 [2]. In this paper, the regulation of HIF - 1 and its expression and significance in ischemic cerebrovascular diseases were reviewed.
1. The structure of HIF - 1
HIF - 1 is the dimer composed of HIF - 1α subunits and HIF - 1β subunits. HIF-1α is functional subunits, HIF-1β is structural subunits. HIF-1α and HIF-1β protein contained spiral - ring - spiral structure, which can make the two subunits form dimers and bind to DNA [3]. Both subunits Contain Per - ARNT - Sim (PAS) domain, with the similar function. HIF-1α subunit contains oxygen-dependent degradation structural domain (ODDD), can be hydroxylated by proline hydroxylase - 2 (PHD - 2), damaging the HIF-1α subunits by protease while oxygen content is normal [4]. HIF-1α contains two active region (TAD), involved in regulating HIF - 1genes for protein of interest. Two Joint activator CREB of HIF - 1 can interact with HIF-1α's carboxyl terminal active region (C - TAD) by binding to protein (CBP) and p300. These two activators are necessary for transcription of HIF - 1, and is also an effective target for HIF expression regulation. There is only one such similar area in HIF-1β, it is not necessary for the function of HIF - 1compound [5].
2. Regulation of HIF - 1
The expression of HIF-1β is not affected by the oxygen content and its mrna and protein maintain at a stable level. While HIF-1α protein has a short half-life, can only survive for up to 5 minutes, and is regulated by the oxygen level [6]. The transcription and expression of HIF-1α are persistent, seems to be not affected by oxygen [7]. But under normal oxygen content, HIF-1α degrades quickly, so that it cannot be measured. In the anoxic condition, HIF-1α become stable, entry into nucleus from the cytoplasm, and form dimers with HIF-1β, this kind of HIF polymer has transcriptional activity [8]. The activated HIF polymers combine with hers of regulating region of target genes, bind Transfer rate activated substance, so as to induce gene expression [9]. The regulation of the stability of HIF-1α and subsequent transcription activation is mainly affected by regulation of post-translational modifications, such as hydroxylation, protein phosphorylation, acetylation and phosphorylation.
The modification of HIF-1α occurs in several areas. Under constant oxygen condition, two proline residue in ODDD area of HIF-1α are hydroxylated, a lysine residue was acetylated, prompt its interaction with von Hippel Lindau - (pvhl) ubiquitin E3 ligase complexs. PVHL will mark ubiquitin by HIF-1α, then degradate it by 26 s proteasome. And the hydroxylation of asparagine residues of C -TAD suppresses the combination of HIF-1α and CBP/p300, inhibiting the transcription activity of HIF - 1 [10].
2.1 PHD proline amide hydroxylation role - ubiquitination signal
After cytoplasm HIF-1α generates, it would be located in ODDD through 2 - keto glutaric acid family-dependent DAO existed in proline 402 (Pro402) and 564 (Pro564), make it rapidly hydroxylated [11]. If two proline residue variate at the same time, the interaction of HIF-1α and pvhl will be blocked, can increase the stability of HIF-1α under oxygen condition, even if only one proline residue variation can increase the stability of HIF-1α [12].
HIF-1α oxidase is the end of PHD, HIF - proline hydroxylase (HPH) or Egg - layingnine (EGLN), and three subtypes have been reported: PHD1 / HPH3 / EGLN2, PHD2 / HPH2 / EGLN1, and PHD3 / HPH1 / EGLN3 [13]. The biochemical characteristics of phds is similar with collagen proline - 4 - hydroxylase, is also 2 - OG-dependent oxidase, need oxygen hydroxylation, at the same time, need Fe2+ and vitamin C as a cofactor [14]. But the collagen proline - 4 - hydroxylase cannot catalyze HIF-1α/HIF-2α hydroxylation. The hydroxylation process decomposes oxygen; One oxygen atom is transfered to proline residue, the other one reacts with 2 - OG to produce succinate and CO2 [11]. Passivation of phds By 2 - OG analogue can extend the half-life of HIF-1α [15]. Fe2+ Existed in phds active site loosely combines with two histidine residues and a nmda, forming 2 - histidine - 1 - carboxylate coordination sequence. Iron and metal chelating agent (such as Co2+, Ni2 -, and Mn2_) can by reducing enzyme can be used for Fe2+ or replace Fe2+ combining Fe2+ binding sites have the effect of alpha stable HIF-1α, proved the phds demand for Fe2+ [11] [16]. Vitamin C can sustain bivalent iron ion (Fe2+) state, is crucial to maintain and achieve phds active state ^[17].
 In vitro three potential hydroxylation of phds HIF - alpha following abilities PHD2 acuity PHD3 > PHD1, PHD2 in carrier cells control HIF - 1 alpha outcome of critical speed [4]. Small interference RNA with specificity can knock out PHD2, in oxygen condition fully stable HIF-1α level, while small interfering RNA silencing PHD1 or PHD3 cannot have a similar effect [18]. And, in the low oxygen change, the mrna of PHD2 and protein was induced, and the mrna of PHD3 were raised, and PHD1 has no change [19]. This could mean a kind of self expression regulation of HIF-1α. In low oxygen situation, Siah1 and Siah 2, PHD1 and PHD 3specificity E3 ligase's expression level is raised, so as to control the degradation of phds by proteasome [20]. When transfection cell marker protein is excessive expressed, PHD2 was found first positioning in cytoplasm, and PHD1 is located in the nucleus, PHD3 is both of above [19]. Although PHD2 is first located in cytoplasm, it can through the cytoplasm and nucleus, so that the degradation of HIF-1α in two parts is achieved. Although these three enzymes are widely expressed in many organizations, they have tissue specificity excessive expression. The expression of PHD2 in fat tissue is the most [21], PHD3 most expressed in the heart and the placenta, PHD1 has a high expression in testis [22]. Different Activity of phds enzyme, subcellular localization and the distribution of tissue may make responses to low oxygen levels has grade and tissue specificity. Many proteins such as OS - 9, produce a lot of unknown function gene expression, it has been proved proline hydroxylation promoted by HIF-1α and phds can increase oxygen dependent HIF-1α degradation [23]. Moreover, many second messengers also showed that modify the activity of phds [24].
 When there is oxygen, phds is active, can hydroxylate proline of HIF-1α, constitute pvhl binded identification signal and the next ubiquitination, then degradate HIF-1α [25]. Under no Oxygen condition, there is no enzyme activation, hydroxylation modified, no pvhl/HIF binding, so HIF-1α is stable and accumulated in a cell. Full Demand for oxygen implies the oxygen sensor effect of phds in a cell [26].
2.2 ubiquitination of PVHL - degradation signaling pathways
Once two proline residue of HIF-1α is decorated by hydroxylation, then pvhl capturehif-1α, pvhl/HIF-1α complex. X-ray crystallography research shows there is a surface pocket in pvhl, hydroxyproline can be closely chimeric with it, and all the binding structure are highly specific [27]. Elongin pvhlproteins elongin C, B, cullin - 2, and Rbx1 form VCB - Cul2 E3 ligase complex. HIF - 1 alpha at the E3 more protein complexes binding to cause HIF - 1 alpha times in protein function, the final degradation by proteasome. But the precise ubiquitination mechanism of lysine residues is still not clear.
PVHL is described for the first time in von Hippel Lindau - (VHL) disease, is a human legacy of the tumor syndrome characterized by multiple tumors, such as clear cell renal carcinoma, pheochromocytoma, retinal cell tumor and central nervous system into blood vessels [28]. VHL gene encoding length (213 amino acids) and N end short protein (54-213 amino acids). Because two proteins showed a similar function, they are often called pvhl. VHL gene mutation, as a product of tumor suppressor gene function, was found in these diseases [29, 30]. In the condition of absence of wild type pvhl cells, HIF-1α and HIF-2α are stable and active when oxygen levels is normal, characterized by excessive gene induced by hypoxia [31]. The function of pvhl is recoverd Through stable transfection, reversing protein stability and genetic abnormalities [31]. PVHL gene mutations cause tumor formation, therefore, may be the mechanism of HIF alpha under normal oxygen environment, the stability and activity of angiogenesis factors led to the subsequent coding gene expression, the role even before the cells exposed to hypoxia environment has occurred.
PVHL E3 ligase complex is ubiquitous in different combinations, mainly concentrated in the cytoplasm. It shuttles within the cytoplasm and nucleus, leading to degradation of HIF-1α of cytoplasm and nucleus (32, 33).
But, pvhl dependent signal pathway may not be the only way to cause HIF-1α degradation. Increase pvhl, a large number of other proteins was reported to affect HIF - 1 alpha times in protein function and stability. For example, Carcinogenic E3 ubiquitin ligase rats double microbody 2 (MDM2) has been considered alpha can cause p53 dependent way HIF - 1 times in protein function [34]. Jab1 as c - Jun and jund transcription and auxiliary activators, can prove again low oxygen increase HIF - 1 alpha level, may compete with p53 in combination with HIF - 1 alpha [35]. And pvhl also proved with other HIF - 1 signaling pathways of protein interaction and regulation might not be the stability of HIF - 1 alpha.
2.3 combination of pvhl is promoted by lysine through ARD1 acetylation
ODDD area lysine residues Positioning HIF-1α was called arrest - defective - 1 (ARD1) acetyltransferase acetylation [36]. ARD1 were first discovered in yeast, its name is derived from the defective yeast cell mitosis. Lys532 acetylation affect HIF - 1 alpha and pvhl interaction, allowing HIF - 1 alpha instability [37]. Lys532 variation for arginine HIF-1α stability increased [38]. And by a acetyl called butyric acid enzyme inhibitors that maintain and increase the HIF - 1 alpha acetylation status, will cause HIF - 1 alpha protein levels [39].
 Because acetyl transferase activity is not affected by oxygen content, ARD1 may activate and acetylate HIF-1α, irrelevant to oxygen. But in the condition of low oxygen, ARD1's mrna and protein levels are low, this may lead to low acetylation of HIF-1α under low oxygen conditions [37].
2.4 CBP/p300 binding is blocked by aspartic acid through hydroxylation of FIH-1
This above HIF-1α modification after translation adjusts stability of HIF-1α protein. But simple stability is not sufficient for HIF - 1 transcription activation. The second main mechanism of control HIF activation is by adjusting its activation region N - TAD and C - TAD. These areas act by transcription auxiliary activation factor such as CBP/p300, SRC - 1, and TIF2 [40]. Under normal oxygen tension, through the factor to inhibit protein HIF - 1 (factor inhibiting HIF - 1, FHI) in HIF - 1 alpha CTD asparagine residues 803 (Asn803) hydroxylation (in HIF - 2 alpha Asn851) stop HIF - 1 alpha interact with CBP/p300 [41]. Hypoxia can cancel asparagine hydroxylation, allow alpha HIF - 1 C - TAD combined with CBP/p300 specific sites, activate the purpose gene transcription [42]. Alanine replacement Asn803 in oxygen condition often HIF - 1 alpha and antioxidant [43]. And reports show FIH - 1 and pvhl combinate up, forming ternary complex with HIF-1α [44]. Although for the activity of FHI - 1 and pvhl interaction is not required, providing the histone acetyl off pvhl enzyme interfere with the transcription process, promote the adjustment of FIH - 1 HIF - 1 alpha turned to live [41]. FIH - 1 mainly exist in the cytoplasm, but seems to be some parts also exists in the nucleus [19]. The transcription of FIH - 1 is not dependent on the oxygen concentration, does not affect the stability of HIF-1α [19].
Similar to PHD, asparagine acyl hydroxylase FIH - 1 is 2 - OG dependent oxidase, also need fe2+ and vitamin C as a cofactor [10]. Using oxygen as a prosthetic group, FIH - 1 can be used as the second oxygen sensor.
2.5 activation is enhanced through MAPK phosphorylation
Although hydroxylase is crucial to sense oxygen tension and regulate the activity of HIF - 1, there will be other control mechanism of HIF - 1. The importance of protein phosphorylation as a control activity is known. The direct phosphorylation of HIF-1α has been reported, mitogen-activated protein kinases(MAPK) pathway seems to account for a major role [45]. P42/44 and p38 kinase can phosphorylate HIF-1α/HIF-2α in vitro [46]. Moreover, p42/44 and p38 kinase inhibitors blocked HIF-1α mediated gene expression [47]. Transfection activity forms of p42/44 kinase can stimulate HIF - 1 alpha transcription activity without affecting the stability of HIF - 1 alpha. And alpha/HIF HIF - 1-2 alpha during hypoxia changes need p42/44 mapks [47]. Seems to be phosphorylated does not affect the stability of HIF - 1 alpha and DNA binding; [48]. One explanation is HIF-1β has priority to combine with phosphorylated HIF-1α [49]. Although function related phosphorylation sites need to identify, threonine 796 of HIF-1α and threonine 844 of HIF-2α is possible sites.
3. Expression and significance of HIF - 1 in ischemic cerebrovascular disease
Ischemia hypoxia Is common in stroke, and studies have shown that during ischemia-reperfusion in rats, different types cells of different areas of the brain have the expression of HIF-1α [50]. The Current research shows that HIF-1α has a dual function of neural protection and apoptosisin in the central nervous system. And whether into survival or promote survival may be related to the type of cell, type of ischemia time and pathological stimulus [51].
3.1 protection function of HIF - 1 on cerebral ischemia
Study of low oxygen protection rats with cerebral ischemia found that the low oxygen and protection can increase the expression of HIF - 1, so as to relieve cerebral edema, reduce blood-brain barrier permeability. HIF - 1 can improve cerebral anoxia tolerance. Deferoxamine, an iron chelating agent,can increase the stability of HIF-1α, act on the cells, in order to enhance the expression of HIF-1α, according to the results, the brain damage area of ischemia rats treated with deferoxamine is reduced by 28%, and the capacity also improve. Neurological score and sensorimotor skills recover early [52].
Studies have shown that HIF target genes EPO and VEGF can inhibit apoptosis, protect the brain tissue. VEGF is the purpose gene of HIF - 1. After cerebral ischemia injury, VEGF are expressed in radial glial cells, neurons, and endothelial cells [53]. VEGF released after cerebral ischemia, play multiple roles through the membrane receptor VEGFR2. Neural precursor cells express VEGFR2 and VEGF by activating VEGF2 stimulating neurogenesis. In stroke model of endogenous and exogenous VEGF can promote neurogenesis [54]. In nerve cell in vitro experiments show that VEGF by induction of neuronal progenitor cells - Mash1 bhlh gene induce the differentiation of neurons [55]. At the same time, VEGF can promote the formation of capillaries collateral circulation after ischemia, increase oxygen tension. Vascular endothelial growth factor (Erythropoietin, EPO) is an early response factors after ischemia. Studies have shown that the effect of EPO may be related to inhibition of excitatory amino acids nerve toxicity and free radical and resistance to apoptosis. At the same time, EPO is significant to the regeneration of neurons. Studies have shown that exogenous EPO can promote regeneration of neurons stroke [56]. The neural cells in vitro experiments show that the differentiation of neurons can be promoted through stimulus of EPO by kinase Akt [57].
3.2 the apoptosis is promoted by HIF - 1
Study shows HIF-1αsirna effect can reduce the infarction area, reduce mortality [58]. Application of HIF-1α activation drugs are also able to protect neurons in vitro and carrier of oxygen [59], showing that HIF - 1 can promote oxygen when the cell death. So HIF - 1 is how to play the role of promoting apoptosis? Studies have shown that neurons after cerebral ischemia death associated with the activation of microglia. In microglia HIF - 1 alpha to hypoxia induced excessive expression of inos play a regulatory role, and the excessive expression of inos, activating with the NO produce, and indirectly promote the death of neurons [60]. Also studies have shown that HIF - 1 alpha from somatic cells can promote apoptosis by regulating gene to promote cell death. Caspase is an important material mediated apoptosis, Alain [61] and other research has shown that after ischemia alpha and procaspase HIF - 1-3 increased performance, show the similar trend. The activated caspase 3 can be seen in cell Expressed by HIF-1α. Electrophoresis tests showed that HIF-1α binding activated the promoter of caspase HIF - 1-3. Shows to promote caspase HIF - 1-3 transcription and promote apoptosis. Studies have shown that in rats after ischemia, apoptosis regulating factors BNIP3 can be detected in cortex neurons and striatum [62]. BNIP3 is a member of the family of the BCL - 2, and associated with immune response caused by ischemia and late-onset cell death. Known BNIP3 HRE sequence is contained in genes, combination in the HRE HIF - 1 to start the gene expression, excessive expression of BNIP3 promote cell death [63].
4. Conclusion
 To sum up, under the condition of constant oxygen, HIF - 1 continues to express but soon degradate, when tissue or cell hypoxia occur, HIF-1α stability and transfer rate activity has improved significantly. The regulation of the stability of HIF-1α and subsequent transcription activation is mainly affected by regulation of post-translational modifications, such as hydroxylation, protein phosphorylation, acetylation and phosphorylation. When appear or hypoxic ischemic cerebrovascular disease the expression of HIF - 1 alpha increased significantly. But its plays a dual role of protection and promote the apoptosis of neurons. What condition can makehif-1α protect or promote apoptosis role, is still not very clear, still remains to be further improved. At the same time, recent studies have shown that BNIP3 mediated cells necrosis apoptosis (Necroptosis), a form similar to necrosis but for the regulation of cell death [64]. The results Prompt HIF-1α may mediate apoptosis of other modes of cell death. The continuous improvement of the research On the function and its mechanism of HIF-1α will provide new theoretical basis and therapeutic targets for the treatment of ischemic brain injury.
 
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