Hydrogen Sulfide Is a Regulator of Hemoglobin Oxygen-Carrying Capacity via Controlling 2,3-BPG Production in Erythrocytes.

ABSTRACT: Hydrogen sulfide (H₂S) is naturally synthesized in a wide range of mammalian tissues. Whether H₂S is involved in the regulation of erythrocyte functions remains unknown. Using mice with a genetic deficiency in a H₂S natural synthesis enzyme cystathionine-?-lyase (CSE) and high-throughput metabolomic profiling, we found that levels of erythrocyte 2,3-bisphosphoglycerate (2,3-BPG), an erythroid-specific metabolite negatively regulating hemoglobin- (Hb-) oxygen (O₂) binding affinity, were increased in CSE knockout (Cse ^-/-) mice under normoxia. Consistently, the 50% oxygen saturation (P50) value was increased in erythrocytes of Cse ^-/- mice. These effects were reversed by treatment with H₂S donor GYY4137. In the models of cultured mouse and human erythrocytes, we found that H₂S directly acts on erythrocytes to decrease 2,3-BPG production, thereby enhancing Hb-O₂ binding affinity. Mouse genetic studies showed that H₂S produced by peripheral tissues has a tonic inhibitory effect on 2,3-BPG production and consequently maintains Hb-O₂ binding affinity in erythrocytes. We further revealed that H₂S promotes Hb release from the membrane to the cytosol and consequently enhances bisphosphoglycerate mutase (BPGM) anchoring to the membrane. These processes might be associated with S-sulfhydration of Hb. Moreover, hypoxia decreased the circulatory H₂S level and increased the erythrocyte 2,3-BPG content in mice, which could be reversed by GYY4137 treatment. Altogether, our study revealed a novel signaling pathway that regulates oxygen-carrying capacity in erythrocytes and highlights a previously unrecognized role of H₂S in erythrocyte 2,3-BPG production.

SUBMITTER: Wang G 

PROVIDER: S-EPMC7896853 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature