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Nitric oxide transport on sickle cell hemoglobin: where does it bind?
M T Gladwin1, F P Ognibene, J H Shelhamer
1Critical Care Medicine Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA. mgladwin@nih.gov
Free Radical Research
|November 8, 2001
Summary
Inhaled nitric oxide (NO) in sickle cell anemia primarily forms nitrosyl hemoglobin (HbFeIINO), not S-nitrosohemoglobin (SNO-Hb). This suggests NO delivery via heme binding is key for potential sickle cell disease therapies.
Area of Science:
- Biochemistry
- Hematology
- Pulmonary Medicine
Background:
- Nitric oxide (NO) inhalation in sickle cell anemia (SCA) increases NO-bound hemoglobin, creating an arterial-venous gradient indicating tissue delivery.
- A proposed model suggests NO forms S-nitrosohemoglobin (SNO-Hb) via cysteine 93, facilitating NO release in tissues to modulate blood flow.
- Previous studies in healthy individuals showed NO primarily forms nitrosyl hemoglobin (HbFeIINO) during NO breathing, with minimal SNO-Hb.
Purpose of the Study:
- To determine if NO is transported as HbFeIINO or SNO-Hb in individuals with sickle cell disease.
- To assess the impact of different NO transport mechanisms on sickle hemoglobin polymerization.
- To investigate the dose-dependent formation of HbFeIINO and SNO-Hb during inhaled NO therapy in SCA.
Main Methods:
- Measurement of HbFeIINO and SNO-Hb levels in three sickle cell volunteers.
- Dose escalation of inhaled NO (40, 60, and 80 ppm) administered to participants.
- Comparison of NO adducts formed in SCA patients with those previously observed in healthy individuals.
Main Results:
- The predominant NO-hemoglobin adduct formed in sickle cell volunteers was HbFeIINO, similar to healthy individuals.
- A significant arterial-venous gradient for HbFeIINO was observed, suggesting effective NO transport.
- Minimal SNO-Hb formation occurred, indicating it is not the primary NO transport pathway in SCA during NO inhalation.
Conclusions:
- NO transport in sickle cell disease during inhalation therapy predominantly occurs via heme binding (HbFeIINO), not S-nitrosylation of cysteine 93 (SNO-Hb).
- The rapid reversibility of NO binding to heme supports a revised model for NO delivery in peripheral circulation.
- Hemoglobin-mediated NO delivery shows potential as a therapeutic strategy for sickle cell disease.
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