SNO-hemoglobin is not essential for red blood cell–dependent hypoxic vasodilation
Open accessAbstract
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.
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A genetic murine model with β93 cysteine replaced by alanine, abolishing SNO-Hb formation, showed no impairment in hypoxic vasodilation, questioning the role of SNO-Hb in physiologic hypoxic vasodilation.
“Additionally, a genetic murine model in which the cysteine 93 of β-Hb was replaced with alanine (and in which SNO-Hb formation was abolished) demonstrated no impairment in hypoxic vasodilation, questioning the role of SNO-Hb in physiologic hypoxic vasodilation (454).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [454]
Cys-93 in the β-subunit of hemoglobin (where S-nitrosohemoglobin is formed) is not essential for RBC-dependent hypoxic vasodilation.
“In contrast, another study demonstrated that Cys-93 in the β-subunit of Hb (where this nitrosothiol is formed) is not essential for RBC-dependent hypoxic vasodilation (83), thus implicating other NO metabolites or pathways.”
From Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia (2017) · cites this paper as [83]
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- Authors
- Isbell, T. S., Sun, C.-W., Wu, L.-C., Teng, X., Vitturi, D. A., Branch, B. G., Kevil, C. G., Peng, N., Wyss, J. M., Ambalavanan, N., Schwiebert, L., Ren, J., Pawlik, K. M., Renfrow, M. B., Patel, R. P., & Townes, T. M.
- Affiliations
- University of Alabama at Birmingham (US)
- Louisiana State University Health Sciences Center Shreveport (US)
- Corresponding author
- Patel, Rakesh P
- Townes, Tim M
- ORCID
- Venue
- Nature Medicine
- Published
- 2008-05-30
- Volume
- 14
- Issue
- 7
- Pages
- 773-777
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC2700065
- OpenAlex
- W2070845549
- Cited by
- 157
- References
- 30
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 8 · 2022: 7 · 2021: 4 · 2020: 3 · 2019: 6 · 2018: 5 · 2017: 5 · 2016: 10 · 2015: 7 · 2014: 7 · 2013: 12 · 2012: 22
- FWCI
- 7.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL057619, HL057619)
- National Institute of Neurological Disorders and Stroke (NS 057098, P30NS057098)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Keywords
- hypoxic vasodilation, nitric oxide, S-nitrosylation, erythrocytes, oxygen sensing, S-nitrosothiols, pulmonary hemodynamics, systemic hemodynamics, mouse model
- MeSH terms
- Animals, Hypoxia, Erythrocytes, Hemodynamics, Hemoglobins, Humans, Nitrates, Nitric Oxide, Nitrites, Oxygen, Vasodilation, Nitrosation, S-Nitrosothiols, Mice
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