Hypoxia-inducible factor as an angiogenic master switch.
Hypoxia-inducible factor as an angiogenic master switch.
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DOI：
10.3389/fped.2015.00033
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发表时间：
2015
影响因子：
2.6
通讯作者：
Shibasaki F
中科院分区：
文献类型：
--
作者：
Hashimoto T;Shibasaki F
缺氧诱导因子（HIF）调节介导缺氧反应的基因转录。 HIF 在常氧条件下持续表达和降解，但在缺氧条件下稳定。 HIF 在生理和病理条件下已被广泛研究，并已被证明有助于各种血管疾病的发病机制。在临床环境中，HIF 通路已被研究其在抑制癌变中的作用。 HIF 也可能在缺血性疾病的病理学中发挥保护作用。施用单一生长因子后治疗性血管生成的临床试验产生了不令人满意或有争议的结果，可能是因为不同 HIF 诱导因子的协调活性对于诱导成熟血管形成是必要的。因此，操纵 HIF 活性以同时诱导一系列血管生成因子为治疗性血管生成提供了一种优越的策略。由于 HIF-2α 在血管重塑中发挥重要作用，因此操纵 HIF-2α 是治疗动脉阻塞引起的缺血性疾病的一种有前途的方法，在这种疾病中，侧支血管发育不足会阻碍有效的治疗。真核起始因子 3 亚基 e (eIF3e)/INT6 与 HIF-2α 特异性相互作用，并诱导 HIF-2α 蛋白酶体抑制剂敏感的降解，不依赖于缺氧和 von Hippel-Lindau 蛋白。即使在含氧量正常的条件下，使用 eIF3e/INT6 siRNA 治疗也能稳定 HIF-2α 活性，并诱导多种血管生成因子的表达，其水平足以在体内产生功能性动脉和静脉。我们已经证明，在动物模型中，对缺血肢体或冷损伤大脑施用 eIF3e/INT6 siRNA 可减少缺血性损伤。本综述总结了目前对 HIF 与血管疾病之间关系的认识。我们还讨论了结合 HIF-α 的新型氧依赖性调节蛋白，以及使用 HIF 稳定剂治疗血管生成的新方法的意义。
Hypoxia-inducible factors (HIFs) regulate the transcription of genes that mediate the response to hypoxia. HIFs are constantly expressed and degraded under normoxia, but stabilized under hypoxia. HIFs have been widely studied in physiological and pathological conditions and have been shown to contribute to the pathogenesis of various vascular diseases. In clinical settings, the HIF pathway has been studied for its role in inhibiting carcinogenesis. HIFs might also play a protective role in the pathology of ischemic diseases. Clinical trials of therapeutic angiogenesis after the administration of a single growth factor have yielded unsatisfactory or controversial results, possibly because the coordinated activity of different HIF-induced factors is necessary to induce mature vessel formation. Thus, manipulation of HIF activity to simultaneously induce a spectrum of angiogenic factors offers a superior strategy for therapeutic angiogenesis. Because HIF-2α plays an essential role in vascular remodeling, manipulation of HIF-2α is a promising approach to the treatment of ischemic diseases caused by arterial obstruction, where insufficient development of collateral vessels impedes effective therapy. Eukaryotic initiation factor 3 subunit e (eIF3e)/INT6 interacts specifically with HIF-2α and induces the proteasome inhibitor-sensitive degradation of HIF-2α, independent of hypoxia and von Hippel-Lindau protein. Treatment with eIF3e/INT6 siRNA stabilizes HIF-2α activity even under normoxic conditions and induces the expression of several angiogenic factors, at levels sufficient to produce functional arteries and veins in vivo. We have demonstrated that administration of eIF3e/INT6 siRNA to ischemic limbs or cold-injured brains reduces ischemic damage in animal models. This review summarizes the current understanding of the relationship between HIFs and vascular diseases. We also discuss novel oxygen-independent regulatory proteins that bind HIF-α and the implications of a new method for therapeutic angiogenesis using HIF stabilizers.
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DOI：
10.1073/pnas.93.23.12969
发表时间：
1996-11-12
影响因子：
11.1
作者：
Arany, Z;Huang, LE;Livingston, DM
通讯作者：
Livingston, DM
影响因子：
7.7
作者：
Alexander, CM;Landsman, PB;Haffner, SM
通讯作者：
Haffner, SM
影响因子：
1.5
作者：
Bai, Chen-Guang;Liu, Xiao-Hong;Ma, Da-Lie
通讯作者：
Ma, Da-Lie
影响因子：
3.3
作者：
Crane, R;Craig, R;Norbury, C
通讯作者：
Norbury, C
影响因子：
4.8
作者：
Chen, Li;Uchida, Kazuyo;Shibasaki, Futoshi
通讯作者：
Shibasaki, Futoshi