Nitrogen monoxide inhibits heme synthesis in mouse reticulocytes

Anemia of infection (AI) often manifests in patients with chronic immune
activation due to cancer, chronic infections, autoimmune disorders, rheumatoid
arthritis and other diseases. The pathogenesis of AI is complex and involves
cytokine-mediated inhibition of erythropoeisis, insufficient erythropoietin production
and diminished sensitivity of erythroid progenitors to this hormone, and retention of
iron in hemoglobin-processing macrophages. Nitric oxide (NO) is a gaseous
molecule produced by activated macrophages that has been identified as having
numerous effects on iron metabolism. Here we explore the possibility that NO affects
iron metabolism in reticulocytes and our results suggest that NO may also contribute
to AI. We treated reticulocytes with the NO donor, sodium nitroprusside (SNP). Our
results indicate that NO inhibits heme synthesis dramatically and rapidly at the level
of erythroid specific 5-aminolevulinic acid synthase 2, which catalyzes the first step
of heme synthesis in erythroid cells. We also show that NO leads to the inhibition of
iron uptake via the transferrin (Tf)-transferrin receptor pathway. In addition, NO also
causes an increase in eIF2α phosphorylation levels and decreases globin translation.
The profound impairment of heme synthesis, iron uptake and globin translation in
reticulocytes by NO raises the possibility that this gas may also contribute to AI.

Source: BJ Energy - January 30, 2013 Category: Biochemistry Authors: M R Mikhael, S Soe-Lin, S S. Apte, P Ponka Tags: BJ Metabolism Source Type: research