The emerging roles of somatic globins in cardiovascular redox biology and beyond
Open accessAbstract
The vertebrate globins are a group of hemoproteins with the intrinsic capacity to regulate gaseous ligands and redox signaling required for cardiovascular biology. This graphical review will provide a comprehensive synopsis of somatic cardiovascular globins focusing on expression, function and redox signaling - an emerging area in both physiology and disease.
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eNOS has been shown to enter the mitochondrion of pulmonary smooth muscle cells upon stimulation with asymmetric dimethyl arginine or endothelin-1.
“For example, eNOS has been shown to enter the mitochondrion of pulmonary smooth muscle cells upon stimulation with asymmetric dimethyl arginine or endothelin-1 (768, 916).”
From Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation (2019) · cites this paper as [768]
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“Graphical Review The emerging roles of somatic globins in cardiovascular redox biology and beyond$ Mizanur M. Rahaman a, Adam C. Straub a,b,n a Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15216, USA b Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15…”
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“Graphical Review The emerging roles of somatic globins in cardiovascular redox biology and beyond$ Mizanur M. Rahaman a, Adam C. Straub a,b,n a Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15216, USA b Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15…”
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“Graphical Review The emerging roles of somatic globins in cardiovascular redox biology and beyond$ Mizanur M. Rahaman a, Adam C. Straub a,b,n a Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15216, USA b Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15…”
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“Historically, Hb has been considered to solely react with NO in a manner to suppress the NO signal through the dioxygenation reaction as described above.”
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“This reaction requires O2 bound Hb. Amazingly, Hb has the capacity to switch from a NO scavenger to a NO synthase under low O2 levels [41].”
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“This reaction requires O2 bound Hb. Amazingly, Hb has the capacity to switch from a NO scavenger to a NO synthase under low O2 levels [41].”
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“Excessive intravascular Hb exposure can result in profound tissue damage by causing lipid peroxide protein modifications and by scavenging NO [49,50].”
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“However, EPR and kinetic studies revealed that the binding of NO to Ngb-Fe2þ is relatively low compared to penta-coordinate Hb and Mb [72].”
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“This reaction requires O2 bound Hb. Amazingly, Hb has the capacity to switch from a NO scavenger to a NO synthase under low O2 levels [41].”
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Hypoxia Up-Regulates Expression of Hemoglobin in Alveolar Epithelial Cells
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“Historically, Hb has been considered to solely react with NO in a manner to suppress the NO signal through the dioxygenation reaction as described above.”
MethodMyoglobin and mitochondria: A relationship bound by oxygen and nitric oxide
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“The reaction with H2O2 leads to Fe4þ– Mb formation, a powerful oxidant that can oxidize proteins and lipids.”
BackgroundInfluentialcGMP-Dependent Activation of Protein Kinase G Precludes Disulfide Activation
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“Hb, composed of α and β chains, was traditionally known for exclusive expression in red blood cells, although a recent reports have dismissed this perception through the discovery of Hb α expression in microvascular endothelial cells [7,8].”
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“Besides oxygen, Hb is well known for its reactivity with NO, a powerful vasodilator [19,20].”
BackgroundIdentification of Myoglobin in Human Smooth Muscle
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“cardiomyocytes and to a much lesser extent vascular smooth muscle [9,53].”
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“Thus it is possible that Hb, particularly in endothelial cells, may have other functions besides control of NO signaling as well as possible roles in reactive oxygen signaling and stress responses.”
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“Hemoglobin also has peroxidative properties when it reacts with oxidants such as hydrogen peroxide (reviewed in [48]).”
BackgroundHemoglobin is an honorary enzyme
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Hemoglobin is expressed in alveolar epithelial type II cells
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“Historically, Hb has been considered to solely react with NO in a manner to suppress the NO signal through the dioxygenation reaction as described above.”
MethodEffects of Cerebral Ischemia on Neuronal Hemoglobin
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“This reaction requires O2 bound Hb. Amazingly, Hb has the capacity to switch from a NO scavenger to a NO synthase under low O2 levels [41].”
BackgroundHaemoglobin expression in human endometrium
Dassen, H. H. N. M., Kamps, R., Punyadeera, C., Dijcks, F. A., de Goeij, A. F. P. M., EDERVEEN, A. G. H., Dunselman, G. A. J., & Groothuis, P. G. (2008) · Human Reproduction · doi:10.1093/humrep/dem430 · Cited by 56 · cited 1× · see citing works
“This reaction requires O2 bound Hb. Amazingly, Hb has the capacity to switch from a NO scavenger to a NO synthase under low O2 levels [41].”
BackgroundLiu, X., Tong, J., Zweier, J. R., Follmer, D., Hemann, C. F., Ismail, R. S., & Zweier, J. L. (2013) · FEBS Journal · doi:10.1111/febs.12352 · Cited by 54 · cited 1× · see citing works
“Expression of Cytb, predominantly in vascular smooth muscle, may likely provide another layer of NO control for vascular tone regulation, especially in the microcirculation.”
BackgroundLow NO Concentration Dependence of Reductive Nitrosylation Reaction of Hemoglobin
Tejero, J., Basu, S., Helms, C. C., Hogg, N., King, S. B., Kim‐Shapiro, D. B., & Gladwin, M. T. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.298927 · Cited by 43 · see citing works
Hemoglobin as a Nitrite Anhydrase: Modeling Methemoglobin‐Mediated N2O3 Formation
Hopmann, K. H., Cardey, B., Gladwin, M. T., Kim‐Shapiro, D. B., & Ghosh, A. (2011) · Chemistry - A European Journal · doi:10.1002/chem.201003578 · Cited by 42 · cited 1× · see citing works
“Excessive intravascular Hb exposure can result in profound tissue damage by causing lipid peroxide protein modifications and by scavenging NO [49,50].”
BackgroundImai, K. (1999) · Nature · doi:10.1038/46707 · Cited by 42 · see citing works
Calcineurin Activates Cytoglobin Transcription in Hypoxic Myocytes
Singh, S., Manda, S. M., Sikder, D. S., Birrer, M. J., Rothermel, B. A., Garry, D. J., & Mammen, P. P. A. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m809572200 · Cited by 41 · cited 3× · see citing works
“may have a functional role in calcium-dependent events accompanying cardiac remodeling [11].”
BackgroundGenerating S-Nitrosothiols from Hemoglobin
Roche, C. J., Cassera, M. B., Dantsker, D., Hirsch, R. E., & Friedman, J. M. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.482679 · Cited by 30 · see citing works
Hemoglobin Expression in Neurons and Glia After Intracerebral Hemorrhage
He, Y., Hua, Y., Keep, R. F., Liu, W., Wang, M. M., & Xi, G. (2011) · Acta neurochirurgica. Supplementum · doi:10.1007/978-3-7091-0693-8_22 · Cited by 15 · cited 1× · see citing works
“This reaction requires O2 bound Hb. Amazingly, Hb has the capacity to switch from a NO scavenger to a NO synthase under low O2 levels [41].”
Background
Flagged first, then by citations
1 of the 74 references couldn’t be matched to a known paper.
Cited by
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Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation
Tejero, J., Shiva, S., & Gladwin, M. T. (2019) · Physiological Reviews · doi:10.1152/physrev.00036.2017 · Cited by 541 · see citing works
Pathogenic implications of distinct patterns of iron and zinc in chronic MS lesions
Popescu, B. F. G., Frischer, J. M., Webb, S. M., Tham, M., Adiele, R. C., Robinson, C. A., Fitz‐Gibbon, P. D., Weigand, S. D., Metz, I., Nehzati, S., et al. (2017) · Acta Neuropathologica · doi:10.1007/s00401-017-1696-8 · Cited by 138 · see citing works
“Alternatively, the heme observed in rarefied gliotic low iron regions may consist of brain globins, which are neuroprotective heme-containing proteins [5, 53].”
Neuronal Hemoglobin Expression and Its Relevance to Multiple Sclerosis Neuropathology
Brown, N. J., Alkhayer, K., Clements, R. J., Singhal, N. K., Gregory, R. B., Azzam, S., Li, S., Freeman, E. J., & McDonough, J. A. (2016) · Journal of Molecular Neuroscience · doi:10.1007/s12031-015-0711-6 · Cited by 66 · see citing works
Hemoglobin α in the blood vessel wall
Butcher, J. T., Johnson, T., Beers, J. M., Columbus, L. M., & Isakson, B. E. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.04.019 · Cited by 45 · see citing works
“However we [3], and others [4,5], have demonstrated that Hbα is expressed in the blood vessel wall but, in contrast to other globins in the blood vessel wall [3,6,7], Hbα localization and physiological effects are concentrated at myoendothelial junctions (MEJs) in the endothelial cells (ECs) lining the lumen of blood…”
BackgroundBrain globins in physiology and pathology
Yang, S., & Xie, L. (2016) · Medical Gas Research · doi:10.4103/2045-9912.191361 · Cited by 45 · see citing works
“Hb protein is assembled into heterotetramers, comprised of two α-globin and two β-globin polypeptides, capable of binding multiple gaseous ligands such as O2, CO, and NO (Rahaman and Straub, 2013).”
BackgroundWalser, M., Svensson, J., Karlsson, L., Motalleb, R., Åberg, M., Kuhn, H. G., Isgaard, J., & Åberg, N. D. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.606089 · Cited by 26 · see citing works
“org 2 myoglobin (Mb), cytoglobin (Cygb), and neuroglobin (Ngb) [for reviews, see (5, 9)].”
BackgroundCellular microdomains for nitric oxide signaling in endothelium and red blood cells
Leo, F., Hutzler, B., Ruddiman, C. A., Isakson, B. E., & Cortese-Krott, M. M. (2020) · Nitric Oxide · doi:10.1016/j.niox.2020.01.002 · Cited by 27 · see citing works
“Although other globin proteins are also expressed within the vascular wall, the discovery of Hbα in the resistance artery endothelium, and specifically at the MEJ, makes its localization to the vascular wall unique compared to other globins endothelium (Figure 2) [81; 82].”
BackgroundZheng, R., Yan, Y., Pu, J., & Zhang, B. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23169088 · Cited by 19 · see citing works
“For instance, only Hb α chains are expressed in endothelial and peripheral catecholaminergic cells, while only β chains are expressed in macrophages [24,25].”
BackgroundRees, M. D., Maiocchi, S. L., Kettle, A. J., & Thomas, S. R. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.03.037 · Cited by 19 · see citing works
Amri, F., Ghouili, I., Tonon, M., Amri, M., & Masmoudi‐Kouki, O. (2017) · Frontiers in Endocrinology · doi:10.3389/fendo.2017.00067 · Cited by 18 · see citing works
The contribution of carbon monoxide to vascular tonus
Koçer, G., Ülker, S. N., & Şentürk, Ü. K. (2018) · Microcirculation · doi:10.1111/micc.12495 · Cited by 18 · see citing works
Lilly, B., Dammeyer, K. L., Marosis, S., McCallinhart, P. E., Trask, A. J., Lowe, M., & Sawant, D. B. (2018) · Vascular Pharmacology · doi:10.1016/j.vph.2018.06.016 · Cited by 15 · see citing works
Tae, B., Oliveira, K. C., da Conceição, R. R., Valenti, V. E., de Souza, J. S., Laureano‐Melo, R., Sato, M. A., Maciel, R. M. B., & Giannocco, G. (2016) · Environmental Toxicology · doi:10.1002/tox.22321 · Cited by 12 · see citing works
Effect of temperature, pH and heme ligands on the reduction of Cygb(Fe3+) by ascorbate
Tong, J., Zweier, J. R., Huskey, R. L., Ismail, R. S., Hemann, C., Zweier, J. L., & Liu, X. (2014) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2014.04.011 · Cited by 11 · see citing works
Escorting α-globin to eNOS: α-globin–stabilizing protein paves the way
Straub, A. C., & Gladwin, M. T. (2018) · Journal of Clinical Investigation · doi:10.1172/jci124302 · Cited by 6 · see citing works
“It has long been considered that hemoglobin expression is exclusive to RBC; however, accumulating evidence continues to demonstrate that α -globin and β -globin are expressed outside of RBC in somatic cells such as neurons, endothelium, and epithelium (2–5).”
Self-citationElectron self-exchange in hemoglobins revealed by deutero-hemin substitution
Athwal, N. S., Alagurajan, J., Sturms, R., Fulton, D. B., Andreotti, A. H., & Hargrove, M. S. (2015) · Journal of Inorganic Biochemistry · doi:10.1016/j.jinorgbio.2015.06.014 · Cited by 6 · see citing works
Can endothelial hemoglobin-α regulate nitric oxide vasodilatory signaling?
Parikh, J., Kapela, A., & Tsoukias, N. M. (2017) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00315.2016 · Cited by 5 · see citing works
Unraveling the Mystery of Hemoglobin in Hypoxia-Accelerated Neurodegenerative Diseases
Tian, Z., Jin, F., Geng, Z., Xu, Z., Shao, Q., Liu, G., Ji, X., & Liu, J. (2025) · Biomolecules · doi:10.3390/biom15091221 · Cited by 2 · see citing works
“Furthermore, endothelial Hb is known to be involved in the clearance of toxic NO [50].”
Structure, function and the related mechanism of cytoglobin
Liu, X., Zhou, D., & Luo, A. (2018) · Scientia Sinica Vitae · doi:10.1360/n052017-00107 · Cited by 1 · see citing works
Clinical strategies to inhibit tumor vascularization
Harris, A. L. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-819494-2.00009-2 · Cited by 1 · see citing works
Gardner, P. R. (2022) · Advances in experimental medicine and biology · doi:10.1007/5584_2022_751 · Cited by 1 · see citing works
Localization of hemoglobin in MS cortex and its relevance to MS neuropathology
Brown, N. J. (2014) · OhioLink ETD Center (Ohio Library and Information Network)
Cui, J., Zhang, Q., Lv, X., Zhao, L., Xu, W., Wang, L., Pei, S., Zhang, W., & Zhuang, M. (2026) · BMC Public Health · doi:10.1186/s12889-026-27247-x
“Furthermore, hemoglobin is present in non-erythroid brain cells, including neurons and glial cells [28], where it serves physiological functions in maintaining mitochondrial activity [10, 29] and mediating the clearance of toxic proteins [30].”
- Authors
- Rahaman, M. M., & Straub, A. C.
- Affiliations
- University of Pittsburgh (US)
- Corresponding author
- Straub, Adam C.
- ORCID
- Straub, Adam C.
- Venue
- Redox Biology
- Publisher
- Elsevier BV
- Published
- 2013
- Volume
- 1
- Issue
- 1
- Pages
- 405-410
- ISSN
- 2213-2317 (ISSN-L)
- PMC
- PMC3814953
- OpenAlex
- W2060044823
- Cited by
- 24
- References
- 74
- Citations by year
- 2026: 1 · 2025: 1 · 2022: 2 · 2021: 1 · 2020: 2 · 2018: 5 · 2017: 3 · 2016: 3 · 2015: 2 · 2014: 4
- FWCI
- 0.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Redox Biology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Institutes of Health (R00HL11290402)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hemoglobin structure and function
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- globin, cardiovascular biology, redox signaling, heme proteins, globin expression, cardiovascular disease
- MeSH terms
- Animals, Cardiovascular System, Globins, Humans, Oxidation-Reduction, Signal Transduction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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