HIF-prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques
HIF-prolyl hydroxylase inhibition results in endogenous erythropoietin induction, erythrocytosis, and modest fetal hemoglobin expression in rhesus macaques
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DOI：
10.1182/blood-2007-02-073254
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发表时间：
2007-09-15
期刊：
影响因子：
20.3
通讯作者：
Tisdale, John F.
中科院分区：
文献类型：
--
作者：
Hsieh, Matthew M.;Linde, N. Seth;Tisdale, John F.
缺氧诱导因子（HIF）通路在减轻缺氧的有害影响中至关重要。HIF-α是氧敏感机制的重要组成部分，在常氧条件下通过HIF-脯氨酰羟化酶的羟基化作用进行降解。几种HIF-脯氨酰羟化酶抑制剂（PHIs）诱导促红细胞生成素（EPO）的表达在体外和小鼠中，与峰值EPO表达范围从5.6到207倍以上的控制动物。此外，如通过流式细胞术测定的，几种PHI在体外诱导原代人红系细胞中的胎儿血红蛋白（HbF）表达。在非人灵长类动物模型中进一步检测了一种PHI（FG-2216）（不伴和伴慢性静脉切开术）。FG-2216具有经口生物利用度，并在体内诱导显著且可逆的Epo诱导（60 mg/kg时为82- 309倍）。雄性恒河猴长期经口给药耐受性良好，显著增加红细胞生成，并预防每周抽血诱导的贫血。此外，通过流式细胞术证实了含HbF的红细胞和网织红细胞的适度增加，但通过高压液相色谱法（HPLC）未证实HbF的显著增加。HIF PHI代表了一类新的分子，其在先天性和获得性贫血中具有广泛的潜在临床应用。
The hypoxia-inducible factor (HIF) pathway is crucial in mitigating the deleterious effects of oxygen deprivation. HIF-alpha is an essential component of the oxygen-sensing mechanisms and under normoxic conditions is targeted for degradation via hydroxylation by HIF-prolyl hydroxylases. Several HIF-prolyl hydroxylase inhibitors (PHIs) induced erythropoietin (epo) expression in vitro and in mice, with peak epo expression ranging from 5.6- to 207-fold above control animals. Furthermore, several PHIs induced fetal hemoglobin (HbF) expression in primary human erythroid cells in vitro, as determined by flow cytometry. One PHI, FG-2216, was further tested in a nonhuman primate model without and with chronic phlebotomy. FG-2216 was orally bioavallable and induced significant and reversible Epo induction in vivo (82- to 309-fold at 60 mg/kg). Chronic oral dosing in male rhesus macaques was well tolerated, significantly increased erythropolesis, and prevented anemia induced by weekly phlebotomy. Furthermore, mod- est increases in HbF-containing red cells and reticulocytes were demonstrated by flow cytometry, though significant increases in HbF were not demonstrated by high-pressure liquid chromatography (HPLC). HIF PHIs represent a novel class of molecules with broad potential clinical application for congenital and acquired anemias.