Molecular mechanisms of action and therapeutic uses of pharmacological inhibitors of HIF-prolyl 4-hydroxylases for treatment of ischemic diseases.
Molecular mechanisms of action and therapeutic uses of pharmacological inhibitors of HIF-prolyl 4-hydroxylases for treatment of ischemic diseases.
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DOI：
10.1089/ars.2013.5186
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发表时间：
2014-06
影响因子：
6.6
通讯作者：
V. Selvaraju;N. Parinandi;R. Adluri;Joshua W Goldman;N. Hussain;J. A. Sánchez;N. Maulik
中科院分区：
文献类型：
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作者：
V. Selvaraju;N. Parinandi;R. Adluri;Joshua W Goldman;N. Hussain;J. A. Sánchez;N. Maulik
意义在这篇综述中，我们讨论了小分子作为脯氨酰羟化酶结构域抑制剂（PHDIs）的疗效和影响。这些化合物的使用导致促血管生成因子和缺氧诱导因子-1 α和-2α（HIF-1α和HIF-2α）的上调，以增强血管生成、糖酵解、红细胞生成和抗凋亡途径，用于治疗导致人类显著发病率和死亡率的各种缺血性疾病。最近的进展从现有的血管系统中长出新的血管和外科手术干预，如冠状动脉搭桥术和支架植入术，已被证明是有效的减轻缺血。然而，氧的初始再进入导致活性氧物质的形成，其引起氧化应激并导致缺血/再灌注（IR）损伤。这种明显的“氧悖论”必须解决以对抗IR损伤。在缺氧期间，PHD活性降低引发HIF-1α的积累和活化，其中PHD和HIF-1α的调节似乎是缺血性疾病的药理学治疗的有希望的治疗靶点。对PHDs和HIF的研究表明，这些分子可以通过调节糖酵解、红细胞生成、细胞凋亡和血管生成作为缺血性疾病的治疗靶点。目前正在努力鉴定和合成更安全的PHD小分子抑制剂，这些抑制剂可以在体内作为治疗缺血性疾病的药物。未来的发展方向这篇综述介绍了现有的小分子PHDIs及其在缺血性疾病治疗中的应用，重点是动物模型中治疗作用的分子机制。
SIGNIFICANCE In this review, we have discussed the efficacy and effect of small molecules that act as prolyl hydroxylase domain inhibitors (PHDIs). The use of these compounds causes upregulation of the pro-angiogenic factors and hypoxia inducible factor-1α and -2α (HIF-1α and HIF-2α) to enhance angiogenic, glycolytic, erythropoietic, and anti-apoptotic pathways in the treatment of various ischemic diseases responsible for significant morbidity and mortality in humans. RECENT ADVANCES Sprouting of new blood vessels from the existing vasculature and surgical intervention, such as coronary bypass and stent insertion, have been shown to be effective in attenuating ischemia. However, the initial reentry of oxygen leads to the formation of reactive oxygen species that cause oxidative stress and result in ischemia/reperfusion (IR) injury. This apparent "oxygen paradox" must be resolved to combat IR injury. During hypoxia, decreased activity of PHDs initiates the accumulation and activation of HIF-1α, wherein the modulation of both PHD and HIF-1α appears as promising therapeutic targets for the pharmacological treatment of ischemic diseases. CRITICAL ISSUES Research on PHDs and HIFs has shown that these molecules can serve as therapeutic targets for ischemic diseases by modulating glycolysis, erythropoiesis, apoptosis, and angiogenesis. Efforts are underway to identify and synthesize safer small-molecule inhibitors of PHDs that can be administered in vivo as therapy against ischemic diseases. FUTURE DIRECTIONS This review presents a comprehensive and current account of the existing small-molecule PHDIs and their use in the treatment of ischemic diseases with a focus on the molecular mechanisms of therapeutic action in animal models.