Free heme regulates placenta growth factor through NRF2-antioxidant response signaling.
Free heme regulates placenta growth factor through NRF2-antioxidant response signaling.
复制标题
游离血红素通过 NRF2 抗氧化反应信号调节胎盘生长因子。
DOI：
10.1016/j.freeradbiomed.2019.08.009
复制
发表时间：
2019
影响因子：
7.4
通讯作者：
Kato,GregoryJ
中科院分区：
文献类型：
--
作者：
Kapetanaki,MariaG;Gbotosho,OluwabukolaT;Sharma,Deva;Weidert,Frances;Ofori-Acquah,SolomonF;Kato,GregoryJ
游离血红素激活成红细胞以表达和分泌胎盘生长因子（PlGF），一种VEGF家族的血管生成肽。在实验动物和镰状细胞病患者中，高循环水平的PlGF与肺动脉高压的超声心动图标记物相关，肺动脉高压是与更强烈的溶血相关的限制生命的并发症。我们现在表明，血红素调节PlGF的机制需要的关键抗氧化反应调节NRF 2的贡献。模拟血红素的作用，NRF 2激动剂萝卜硫素刺激培养的人成红细胞样细胞中的PlGF转录水平近30倍。血红素和萝卜硫素还诱导NRF 2本身、其伙伴MAFF和MAFG以及其竞争对手BACH 1的转录。此外，PIGF转录物的血红素诱导被NRF 2抑制剂布鲁沙醇和NRF 2和/或MAFG转录因子的siRNA敲低显著减少。染色质免疫沉淀实验表明，血红素诱导NRF 2直接结合到PlGF启动子区。在补充体内实验中，注射血红素的小鼠早在治疗后3小时就显示出其血浆PlGF蛋白的显著增加。我们的研究结果揭示了PlGF调节的重要机制，增加了支持NRF 2轴在镰状细胞病病理生物学中的关键重要性的越来越多的文献。
Free heme activates erythroblasts to express and secrete Placenta Growth Factor (PlGF), an angiogenic peptide of the VEGF family. High circulating levels of PlGF have been associated in experimental animals and in patients with sickle cell disease with echocardiographic markers of pulmonary hypertension, a life-limiting complication associated with more intense hemolysis. We now show that the mechanism of heme regulation of PlGF requires the contribution of the key antioxidant response regulator NRF2. Mimicking the effect of heme, the NRF2 agonist sulforaphane stimulates the PlGF transcript level nearly 30-fold in cultured human erythroblastoid cells. Heme and sulforaphane also induce transcripts for NRF2 itself, its partners MAFF and MAFG, and its competitor BACH1. Furthermore, heme induction of the PlGF transcript is significantly diminished by the NRF2 inhibitor brusatol and by siRNA knockdown of the NRF2 and/or MAFG transcription factors. Chromatin immunoprecipitation experiments show that heme induces NRF2 to bind directly to the PlGF promoter region. In complementaryin vivoexperiments, mice injected with heme show a significant increase in their plasma PlGF protein as early as 3 h after treatment. Our results reveal an important mechanism of PlGF regulation, adding to the growing literature that supports the pivotal importance of the NRF2 axis in the pathobiology of sickle cell disease.