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Human red blood cells at work: identification and visualization of erythrocytic eNOS activity in health and disease
Open accessAbstract
A nitric oxide synthase (NOS)–like activity has been demonstrated in human red blood cells (RBCs), but doubts about its functional significance, isoform identity and disease relevance remain. Using flow cytometry in combination with the nitric oxide (NO)–imaging probe DAF-FM we find that all blood cells form NO intracellularly, with a rank order of monocytes > neutrophils > lymphocytes > RBCs > platelets. The observation of a NO-related fluorescence within RBCs was unexpected given the abundance of the NO-scavenger oxyhemoglobin. Constitutive normoxic NO formation was abolished by NOS inhibition and intracellular NO scavenging, confirmed by laser-scanning microscopy and unequivocally validated by detection of the DAF-FM reaction product with NO using HPLC and LC-MS/MS. Using immunoprecipitation, ESI-MS/MS-based peptide sequencing and enzymatic assay we further demonstrate that human RBCs contain an endothelial NOS (eNOS) that converts L-3H-arginine to L-3H-citrulline in a Ca2+/calmodulin-dependent fashion. Moreover, in patients with coronary artery disease, red cell eNOS expression and activity are both lower than in age-matched healthy individuals and correlate with the degree of endothelial dysfunction. Thus, human RBCs constitutively produce NO under normoxic conditions via an active eNOS isoform, the activity of which is compromised in patients with coronary artery disease.
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“a number of recent studies using chimeric cross bone marrow transplant mouse models have shown that the red blood cell also expresses a functional eNOS that contributes in part to systemic blood pressure responses”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [181]
In the citing paper
“Recently, the NOS in RBCs was identified as a catalytically active eNOS (NOS3 type 1), which is identical to the eNOS expressed in endothelium, as assessed by immunoprecipitation and liquid chromatography mass spectroscopy (40), and confirmed by others through the analysis of conversion of L-15N-arginine into L-15N-citrulline (52).”
From Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia (2017) · cites this paper as [40]
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“Additionally, according to basic science studies, RBCs may control systemic hemodynamics by influencing blood rheological properties and contribute to tissue protection and cardiovascular homeostasis (40, 73, 82).”
From Red Blood Cell Function and Dysfunction: Redox Regulation, Nitric Oxide Metabolism, Anemia (2017) · cites this paper as [40]
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Metadata
- Authors
- Cortese-Krott, M. M., Rodriguez-Mateos, A., Sansone, R., Kuhnle, G. G. C., Thasian-Sivarajah, S., Krenz, T., Horn, P., Krisp, C., Wolters, D., Heiß, C., Kröncke, K.-D., Hogg, N., Feelisch, M., & Kelm, M.
- Affiliations
- Heinrich Heine University Düsseldorf (DE)
- Department of Food and Nutritional Sciences, University of Reading, Reading, United Kingdom;
- University of Reading (GB)
- Ruhr University Bochum (DE)
- Medical College of Wisconsin (US)
- Southampton General Hospital (GB)
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2012-11-15
- Volume
- 120
- Issue
- 20
- Pages
- 4229-4237
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W1968569934
- Cited by
- 183
- References
- 50
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 12 · 2023: 15 · 2022: 8 · 2021: 20 · 2020: 17 · 2019: 14 · 2018: 11 · 2017: 8 · 2016: 17 · 2015: 15 · 2014: 14 · 2013: 16
- FWCI
- 9.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Blood (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- Open Research (University of Surrey) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Honeywell Federal Manufacturing and Technologies
- Topics
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
- Keywords
- erythrocytes, endothelial nitric oxide synthase, nitric oxide production, coronary artery disease, endothelial dysfunction, nitric oxide scavenging, oxyhemoglobin
- MeSH terms
- Adult, Amino Acid Sequence, Arginine, Chromatography, High Pressure Liquid, Citrulline, Coronary Artery Disease, Endothelium, Vascular, Erythrocytes, Flow Cytometry, Fluoresceins, Fluorescent Dyes, Humans, Molecular Sequence Data, Nitric Oxide, Oxyhemoglobins, Mass Spectrometry, Sequence Alignment, Sequence Homology, Amino Acid, Microscopy, Confocal, NG-Nitroarginine Methyl Ester, Sequence Analysis, Protein, Immunoprecipitation, Nitric Oxide Synthase Type III
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