Journal
BLOOD
Volume 107, Issue 2, Pages 566-574Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2005-07-2668
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Funding
- Intramural NIH HHS Funding Source: Medline
- NHLBI NIH HHS [HL70146, HL-24525] Funding Source: Medline
- NIGMS NIH HHS [T32 GM08361] Funding Source: Medline
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Local vasodilation in response to hypoxia is a fundamental physiologic response ensuring oxygen delivery to tissues under metabolic stress. Recent studies identify a role for the red blood cell (RBC), with hemoglobin the hypoxic sensor. Herein, we investigate the mechanisms regulating this process and explore the relative roles of adenosine triphosphate, S-nitrosohemoglobin, and nitrite as effectors. We provide evidence that hypoxic RBCs mediate vasodilation by reducing nitrite to nitric oxide (NO) and ATP release. NO dependence for nitrite-mediated vasodilation was evidenced by NO gas formation, stimulation of cGMP production, and inhibition of mitochondrial respiration in a process sensitive to the NO scavenger C-PTIO. The nitrite reductase activity of hemoglobin is modulated by heme deoxygenation and heme redox potential, with maximal activity observed at 50% hemoglobin oxygenation (P-50). Concomitantly, vasodilation is initiated at the P-50, suggesting that oxygen sensing by hemoglobin is mechanistically linked to nitrite reduction and stimulation of vasodilation. Mutation of the conserved beta 93cys residue decreases the heme redox potential (ie, decreases E-1/2), an effect that increases nitrite reductase activity and vasodilation at any given hemoglobin saturation. These data support a function for RBC hemoglobin as an allosterically and redox-regulated nitrite reductase whose enzyme activity couples hypoxia to increased NO-dependent blood flow.
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