缺氧诱导因子-1和缺氧诱导因子-2：结构、功能及调节

缺氧诱导因子-1（HIF-1）和缺氧诱导因子-2（HIF-2）是细胞应对缺氧时关键的转录因子,在生物体生理及病理过程中有重要的作用。HIF由一个α亚基和一个β亚基组成二聚体。在蛋白水平上,HIF的稳定性及转录活性受到多种机制的调控,除为人所熟知的O2/PHDs/pVHL降解途径及FIH-1羟基化作用外,分别针对HIF-1α和HIF-2α的特异性调控机制也相继被报道。从HIF-1α和HIF-2α的蛋白结构、稳定性调控、转录激活功能以及两者在细胞代谢、肿瘤发生中的作用等方面对两者的相似性和差异性进行综述。     

The Factor Inhibiting HIF Asparaginyl Hydroxylase Regulates Oxidative Metabolism and Accelerates Metabolic Adaptation to Hypoxia

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HIF2A Variants Were Associated with Different Levels of High-Altitude Hypoxia among Native Tibetans

Hypoxia inducible factors, including HIF1A and HIF2A, play central roles in response to high-altitude hypoxia and genetic variants of HIF1A or HIF2A were associated with high-altitude sickness or adaptation. However, it remains to determine whether they are associated with tolerance to different levels of high-altitude selection pressure among native Tibetans. We recruited 189 Tibetan subjects living at 2,700 meters (Low level of high altitude, LHA), 197 at 3,200 meters (Middle level of high altitude of high altitude, MHA), 249 at 3,700 meters (High level of high altitude, HHA) and 269 at 4,700 meters (Very high level of high altitude, VHA) and performed association analysis of twelve tSNPs (tagging SNPs) in HIF1A and HIF2A with high-altitude. We found (1) a increasing trend of HIF2A rs5621780-C(18.4%, 15.9%, 32.8% and 31.1%, respectively, in LHA, MHA, HHA and VHA)(P = 3.56E-9); (2) increasing trends of HIF2A rs6756667-A(68.7%, 73.4%, 79.9% and 89.6%), rs7589621- G(74.6%, 77.9%, 83.7%, and 92.1%) and rs1868092-A(64.1%, 67.3%, 75.1% and 84.4%) (P = 3.56E-9, 4.68E-16, 1.17E-13 and 7.09E-14, respectively); (3) a increasing trend of haplotype AG (68.7%, 73.1%, 79.9% and 89.6%) (P = 2.22E-7) which was constructed by rs6756667 and rs7589621; (4) a strong linear correlation between major alleles of rs6756667-A (R ² = 0.997, P = 0.002), rs7589621-G (R ² = 0.994, P = 0.003), rs1868092-A (R ² = 0.985, P = 0.008) and altitude by linear correlation test. The associations between HIF2A variants and different level of high altitude support that extremely high-altitude hypoxia challenge imposes selective effects on HIF2A variants among native Tibetans.     

Hypoxia induces apoptosis in SV40-immortalized rat proximal tubular cells through the mitochondrial pathways,devoid of HIF1-mediated upregulation of Bax

Chronic hypoxia is a major contributor to tubulointerstitial injury in various renal diseases and apoptosis is apparently involved. Although many studies report hypoxia-induced apoptosis in cultured tubular cells, information has been limited in proximal tubular cells, those from the most susceptible portion of renal tubules against hypoxia. This study was to confirm a role for apoptosis in hypoxic proximal tubular cells and to investigate its association with HIF-1. Temperature-sensitive SV40-immortalized rat proximal tubular cells (IRPTCs) showed apoptosis in 21.9+/-2.9% by hypoxia (0.2% O(2), 48h), with alterations in mitochondrial signaling such as Bcl2 and caspase-9. Bax mRNA was unaffected during the process. However, treating IRPTCs at the nonpermissive temperature showed an upregulation of Bax by hypoxia, which was abrogated by overexpressing dominant-negative HIF-1alpha. These findings extend previous reports on hypoxia-mediated tubular cell apoptosis and demonstrate the possible involvement of HIF-1 as an upstream molecule of Bax.     

Hypoxia, hyperoxia and breathing

Conclusions This short Commentary has been limited to a few of several studies. They clearly indicate that the mechanisms involved in the effects of hypoxia and hyperoxia on the ventilatory control and particularly on theintegrative respiratory centres are far from being completely understood and are now believed to be more complex than what was postulated 40 years ago. Other mechanisms, which are beyond the scope of this short review, are currently the subjects of numerous studies which suggest that mediators or modulators are involved not only at the periphery but also at the level of the central nervous system. It must be emphasized that all these recent studies do not contradict at all, but rather help to explain, the early findings of Pierre Dejours concerning the participation of the peripheral chemoreceptors in the regulation and control of breathing.     

Siah proteins, HIF prolyl hydroxylases, and the physiological response to hypoxia

New evidence suggests that at least two members of the family of hypoxia-inducible factor (HIF) prolyl hydroxylases that regulate HIF stability in response to oxygen (O2) availability are also targeted for proteosome-dependent degradation by the E3 ubiquitin ligases Siah1a and Siah2. This preview examines cellular responses to O2 deprivation (hypoxia) and the complexity of the regulation of the HIF O2 sensing pathway in mammals.     

Hypoxia,MTOR and autophagy

Although hypoxia can cause cell cycle arrest, it may simultaneously suppress a conversion from this arrest to senescence. Furthermore, hypoxia can suppress senescence caused by diverse stimuli, maintaining reversible quiescence instead. Hypoxia activates autophagy and inhibits MTOR, thus also activating autophagy. What is the relationship between autophagy and cellular senescence? Also, can inhibition of MTOR and stimulation of autophagy explain the gerosuppressive effects of hypoxia?     

Hypoxia, leukocytes, and the pulmonary circulation.

Data are rapidly accumulating in support of the idea that circulating monocytes and/or mononuclear fibrocytes are recruited to the pulmonary circulation of chronically hypoxic animals and that these cells play an important role in the pulmonary hypertensive process. Hypoxic induction of monocyte chemoattractant protein-1, stromal cell-derived factor-1, vascular endothelial growth factor-A, endothelin-1, and tumor growth factor-beta(1) in pulmonary vessel wall cells, either directly or indirectly via signals from hypoxic lung epithelial cells, may be a critical first step in the recruitment of circulating leukocytes to the pulmonary circulation. In addition, hypoxic stress appears to induce release of increased numbers of monocytic progenitor cells from the bone marrow, and these cells may have upregulated expression of receptors for the chemokines produced by the lung circulation, which thus facilitates their specific recruitment to the pulmonary site. Once present, macrophages/fibrocytes may exert paracrine effects on resident pulmonary vessel wall cells stimulating proliferation, phenotypic modulation, and migration of resident fibroblasts and smooth muscle cells. They may also contribute directly to the remodeling process through increased production of collagen and/or differentiation into myofibroblasts. In addition, they could play a critical role in initiating and/or supporting neovascularization of the pulmonary artery vasa vasorum. The expanded vasa network may then act as a conduit for further delivery of circulating mononuclear cells to the pulmonary arterial wall, creating a feedforward loop of pathological remodeling. Future studies will need to determine the mechanisms that selectively induce leukocyte/fibrocyte recruitment to the lung circulation under hypoxic conditions, their direct role in the remodeling process via production of extracellular matrix and/or differentiation into myofibroblasts, their impact on the phenotype of resident smooth muscle cells and adventitial fibroblasts, and their role in the neovascularization observed in hypoxic pulmonary hypertension.     

Placenta Percreta and the Urologist

Placenta percreta, the rarest and most severe form of placenta accreta, can involve the urinary bladder. Because of its propensity for severe hemorrhage, it is a potentially life-threatening condition. Although commonly discovered at the time of delivery, antenatal diagnosis may be achieved with ultrasound, magnetic resonance imaging, and/or cystoscopy. Every attempt should be made to minimize potential for blood loss by avoiding removal of the placenta at the time of delivery and either performing a hysterectomy or using methotrexate therapy to ablate the residual placenta in the postpartum period. If hemorrhage does occur during delivery, immediate surgical removal of the uterus should be considered and, depending on the severity of the hemorrhage and the depth of invasion of the placenta into the bladder, excision and/or reconstruction of the bladder may be necessary.Key words: Placenta percreta, Placenta accreta, Bladder invasionMajor obstetric hemorrhage is the leading cause of maternal morbidity and mortality.¹ In rare cases, life-threatening hemorrhage in pregnant women may result from abnormal invasion of the bladder by the placenta. Retained placental membranes and tissues are responsible for 5% to 10% of postpartum hemorrhages. Normally, a layer of decidua separates the placental villi and the myometrium (the inner layer of the uterus) at the site of placental implantation. When the placenta directly adheres to the myometrium without the presence of an intervening decidua, this condition is known as placenta accreta, which is one cause of retained placental tissue.Placenta accreta is classified according to its degree of invasion into the myometrium (Figure 1): placenta accreta vera, placenta increta, and placenta percreta. Placenta accreta vera is a term used to denote a placenta with villi that adhere to the superficial myometrium. Placenta increta occurs when the villi adhere to the body of the myometrium, but not through its full thickness. Placenta percreta occurs when the villi penetrate the full thickness of the myometrium and may invade neighboring organs such as the bladder or the rectum. Although the exact cause of placenta accreta is unknown, it is associated with several clinical situations such as previous cesarean delivery, placenta previa, grand multiparity, previous uterine curettage, and previously treated Asherman syndrome, which is a condition characterized by the presence of scars within the uterine cavity.²Open in a separate windowFigure 1Placenta accreta is classified according to the degree of invasion into the myometrium.

Table 1

Classification of Placenta Accreta by Degree of Invasion