ReferenceID 3867
Free heme regulates placenta growth factor through NRF2-antioxidant response signaling
Free Radic Biol Med
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 patien
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Record Fields
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- Reference Id
- 3867
- Evidence Id
- 20457
- Core Evidence Id
- 20457
- Source Reference Id
- 1024
- Herb2 Reference Id
- HBREF001748
- Subject Paper Key
- HBIN018930_31408727
- Pubmed Id
- 31408727
- Doi
- 10.1016/j.freeradbiomed.2019.08.009
- Paper Title
- Free heme regulates placenta growth factor through NRF2-antioxidant response signaling
- Paper Abstract
- 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 complementary in vivo experiments, 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.
- Journal
- Free Radic Biol Med
- Publish Year
- 2019
- Experiment Subject
- human erythroblastoid cells
- Experiment Type
- Cell Experiment
- Phenotype Related
- Paper Title Cn
- Paper Title En
- Free heme regulates placenta growth factor through NRF2-antioxidant response signaling
- Bilingual Status
- semi_complete