Crawford 2006 Blood

Crawford JH, Isbell TS, Huang Z, Shiva S, Chacko BK, Schechter AN, Darley-Usmar VM, Kerby JD, Lang JD Jr, Kraus D, Ho C, Gladwin MT, Patel RP (2006) Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation. Blood 107:566-74.

» PMID: 16195332 Open Access

Crawford JH, Isbell TS, Huang Z, Shiva S, Chacko BK, Schechter AN, Darley-Usmar VM, Kerby JD, Lang JD Jr, Kraus D, Ho C, Gladwin MT, Patel RP (2006) Blood

Abstract: 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 (p₅₀). Concomitantly, vasodilation is initiated at the p₅₀, suggesting that oxygen sensing by hemoglobin is mechanistically linked to nitrite reduction and stimulation ofvasodilation. Mutation of the conserved β93cys residue decreases the heme redox potential (ie, decreases E1/2), 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.

• O2k-Network Lab: US AL Birmingham Kraus DW

Labels: MiParea: Respiration, Genetic knockout;overexpression 

Stress:Ischemia-reperfusion, Oxidative stress;RONS  Organism: Rat  Tissue;cell: Blood cells  Preparation: Isolated mitochondria 

HRR: Oxygraph-2k