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SNO-hemoglobin is not essential for red blood cell-dependent hypoxic vasodilation.

ABSTRACT: The coupling of hemoglobin sensing of physiological oxygen gradients to stimulation of nitric oxide (NO) bioactivity is an established principle of hypoxic blood flow. One mechanism proposed to explain this oxygen-sensing-NO bioactivity linkage postulates an essential role for the conserved Cys93 residue of the hemoglobin beta-chain (betaCys93) and, specifically, for S-nitrosation of betaCys93 to form S-nitrosohemoglobin (SNO-Hb). The SNO-Hb hypothesis, which conceptually links hemoglobin and NO biology, has been debated intensely in recent years. This debate has precluded a consensus on physiological mechanisms and on assessment of the potential role of SNO-Hb in pathology. Here we describe new mouse models that exclusively express either human wild-type hemoglobin or human hemoglobin in which the betaCys93 residue is replaced with alanine to assess the role of SNO-Hb in red blood cell-mediated hypoxic vasodilation. Substitution of this residue, precluding hemoglobin S-nitrosation, did not change total red blood cell S-nitrosothiol abundance but did shift S-nitrosothiol distribution to lower molecular weight species, consistent with the loss of SNO-Hb. Loss of betaCys93 resulted in no deficits in systemic or pulmonary hemodynamics under basal conditions and, notably, did not affect isolated red blood cell-dependent hypoxic vasodilation. These results demonstrate that SNO-Hb is not essential for the physiologic coupling of erythrocyte deoxygenation with increased NO bioactivity in vivo.

SUBMITTER: Isbell TS

PROVIDER: S-EPMC2700065 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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SNO-hemoglobin is not essential for red blood cell-dependent hypoxic vasodilation.

Isbell T Scott TS Sun Chiao-Wang CW Wu Li-Chen LC Teng Xinjun X Vitturi Dario A DA Branch Billy G BG Kevil Christopher G CG Peng Ning N Wyss J Michael JM Ambalavanan Namasivayam N Schwiebert Lisa L Ren Jinxiang J Pawlik Kevin M KM Renfrow Matthew B MB Patel Rakesh P RP Townes Tim M TM

Nature medicine 20080530 7

The coupling of hemoglobin sensing of physiological oxygen gradients to stimulation of nitric oxide (NO) bioactivity is an established principle of hypoxic blood flow. One mechanism proposed to explain this oxygen-sensing-NO bioactivity linkage postulates an essential role for the conserved Cys93 residue of the hemoglobin beta-chain (betaCys93) and, specifically, for S-nitrosation of betaCys93 to form S-nitrosohemoglobin (SNO-Hb). The SNO-Hb hypothesis, which conceptually links hemoglobin and NO ...[more]

PMID: 18516054

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Project description:Abnormally shaped red blood cells (RBCs), called poikilocytes, can cause anemia. At present, the biochemical abnormalities in poikilocytes are not well understood. Normal RBCs and poikilocytes were analyzed using whole-blood and single-cell methods. Poikilocytes were induced in rat blood by intragastrically administering titanium dioxide (TiO2) nanoparticles. Complete blood count and inductively coupled plasma mass spectrometry analyses were performed on whole-blood to measure average RBC morphology, blood hemoglobin (HGB), iron content, and other blood parameters. Follow-up confocal Raman spectroscopy was performed on single RBCs to analyze cell-type-specific HGB content. Two types of poikilocytes, acanthocytes and echinocytes, were observed in TiO2 blood samples, along with normal RBCs. Acanthocytes (diameter 7.7??±??0.5???m) and echinocytes (7.6??±??0.6???m) were microscopically larger (p??<??0.05) than normal RBCs (6.6??±??0.4???m) found in control blood samples (no TiO2 administration). Similarly, mean corpuscular volume was higher (p??<??0.05) in TiO2 whole-blood (70.70??±??1.97??fl) than in control whole-blood (67.42??±??2.03??fl). Poikilocytes also had higher HGB content. Mean corpuscular hemoglobin was higher (p??<??0.05) in TiO2 whole-blood (21.84??±??0.75??pg) than in control whole-blood (20.8??±??0.32??pg). Iron content was higher (p??<??0.001) in TiO2 whole-blood (697.0??±??24.5??mg??/??l) than in control whole-blood (503.4??±??38.5??mg??/??l), which supports elevated HGB as iron is found in HGB. HGB-associated Raman bands at 1637, 1585, and 1372??cm??-??1 had higher (p??<??0.001) amplitudes in acanthocytes and echinocytes than in RBCs from control blood and normal RBCs from TiO2 blood. Further, the 1585-cm??-??1 band had a lower (p??< ?0.05) amplitude in normal RBCs from TiO2 versus control RBCs. This represents biochemical abnormalities in normal appearing RBCs. Overall, poikilocytes, especially acanthocytes, have elevated HGB.

Dataset Information

SNO-hemoglobin is not essential for red blood cell-dependent hypoxic vasodilation.

Publications

SNO-hemoglobin is not essential for red blood cell-dependent hypoxic vasodilation.

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