Free heme regulates placenta growth factor through NRF2-antioxidant response signaling

Free Radic Biol Med. 2019 Nov 1;143:300-308. doi: 10.1016/j.freeradbiomed.2019.08.009. Epub 2019 Aug 10.

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.

Keywords: NRF2; Oxidative stress; Placenta growth factor; Pulmonary hypertension; Sickle cell disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antioxidant Response Elements / genetics*
  • Antioxidants / metabolism*
  • Female
  • Gene Expression Regulation*
  • Heme / pharmacology*
  • MafG Transcription Factor / genetics
  • MafG Transcription Factor / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-E2-Related Factor 2 / physiology*
  • Oxidative Stress
  • Placenta Growth Factor / genetics*
  • Placenta Growth Factor / metabolism
  • Promoter Regions, Genetic
  • Signal Transduction

Substances

  • Antioxidants
  • MafG Transcription Factor
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Placenta Growth Factor
  • Heme