Nitric Oxide Transport in Blood: A Third Gas in the Respiratory Cycle

Doctor, Allan; Stamler, Jonathan S.

doi:10.1002/cphy.c090009

Cited by 69 publications

(95 citation statements)

References 317 publications

(486 reference statements)

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“…Furthermore, declines in SNO-Hb in hypoxic RBCs were commensurate with measured release of bioactive SNOs (29). SNO-Hb is thus in equilibrium with the small molecular weight SNOs that mediate vasodilation (16,17,20,30). It was subsequently shown that ATP released from RBCs can also relax blood vessels (48,49), albeit through an endothelium-dependent mechanism.…”

Section: Discussionmentioning

confidence: 86%

“…However, nitrite is a nuance of the SNO-based mechanism (16,24) [not a rejection of it as originally put forth by Cosby et al (50)] because nitrite acts as a precursor to SNO-Hb formation (16,17,27,28,51). Indeed, initial claims that free NO derived from nitrite could escape the hemes in Hb to elicit vasodilation independently of SNOs (50) have not been reproduced (even by the authors themselves) (52)(53)(54), and were likely an in vitro artifact of reagents added to the bioassay system (16,24,52,53). These same proponents of a SNO-independent role for nitrite have claimed that hypoxic vasodilation was unaltered in Cysβ93-deficient mice refractory to SNO-Hb formation (41).…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, it is proposed that the conformational changes incurred upon binding and release of O 2 from the hemes are intimately linked to binding and release of NO from cysteine residues in Hb, and that the released NO is liberated from RBCs in the form of bioactive S-nitrosothiols (SNOs). There is further appreciation that NO derived from nitrite may participate in RBC vasodilation through its conversion into SNOs (16,17,27,28). [Note, however, that NO itself cannot escape sequestration by excess hemes of Hb (24).]…”

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confidence: 99%

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S-nitrosylation therapy to improve oxygen delivery of banked blood

Reynolds¹,

Bennett²,

Cina

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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From the perspectives of disease transmission and sterility maintenance, the world's blood supplies are generally safe. However, in multiple clinical settings, red blood cell (RBC) transfusions are associated with adverse cardiovascular events and multiorgan injury. Because ∼85 million units of blood are administered worldwide each year, transfusion-related morbidity and mortality is a major public health concern. Blood undergoes multiple biochemical changes during storage, but the relevance of these changes to unfavorable outcomes is unclear. Banked blood shows reduced levels of S-nitrosohemoglobin (SNO-Hb), which in turn impairs the ability of stored RBCs to effect hypoxic vasodilation. We therefore reasoned that transfusion of SNO-Hb-deficient blood may exacerbate, rather than correct, impairments in tissue oxygenation, and that restoration of SNO-Hb levels would improve transfusion efficacy. Notably in mice, administration of banked RBCs decreased skeletal muscle pO 2 , but infusion of renitrosylated cells maintained tissue oxygenation. In rats, hemorrhage-induced reductions in muscle pO 2 were corrected by SNO-Hb-repleted RBCs, but not by control, stored RBCs. In anemic awake sheep, stored renitrosylated, but not control RBCs, produced sustained improvements in O 2 delivery; in anesthetized sheep, decrements in hemodynamic status, renal blood flow, and kidney function incurred following transfusion of banked blood were also prevented by renitrosylation. Collectively, our findings lend support to the idea that transfusions may be causally linked to ischemic events and suggest a simple approach to prevention (i.e., SNO-Hb repletion). If these data are replicated in clinical trials, renitrosylation therapy could have significant therapeutic impact on the care of millions of patients.ethyl nitrite | hemoglobin cysbeta93 | nitric oxide | storage lesion

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Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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S-nitrosylation therapy to improve oxygen delivery of banked blood

Reynolds¹,

Bennett²,

Cina

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Although hemoglobin is best known for its role as an oxygen carrier in erythrocytes, many biological functions of hemoglobin predate the evolution of the circulatory system and are used to modulate various redox functions and interactions with gaseous transmitters such as nitric oxide (NO) and hydrogen sulfide (H 2 S) (1)(2)(3)(4)(5). For instance, clams living in H 2 S-rich waters upregulate intracellular hemoglobin levels as a protective mechanism against H 2 S toxicity (5).…”

Section: Introductionmentioning

confidence: 99%

Upregulation and Mitochondrial Sequestration of Hemoglobin Occur in Circulating Leukocytes during Critical Illness, Conferring a Cytoprotective Phenotype

Brunyánszki

Erdélyi

Szczesny

et al. 2015

Mol Med

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“…Numerous RBC functions cycle with pO 2 during circulation because of regulation by Hb-conformation-dependent control of the cdB3-based protein assembly, including: ion and amino acid transport, 10 cytoskeleton-membrane interaction, 11 processing/ export of vasoactive effectors (eg, NO), [12][13][14] and glycolysis. 8 Accumulating evidence now affords detailed understanding of such cycling in glycolysis, in which the Embden Meyerhof pathway (EMP) flux is linked to O 2 gradients via a reciprocal binding relationship between key EMP enzymes and deoxy-Hb for regulatory sites on cdB3.…”

Section: Introductionmentioning

confidence: 99%

Sickle hemoglobin disturbs normal coupling among erythrocyte O2 content, glycolysis, and antioxidant capacity

Rogers¹,

Ross²,

Davignon

et al. 2013

Blood

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Key Points• Hb-conformation-dependent interaction with band 3 protein regulates glycolysis in RBCs.• In hypoxia, HbS disrupts this system, disabling RBC antioxidant defense. Energy metabolism in RBCs is characterized by O 2 -responsive variations in flux through the Embden Meyerhof pathway (EMP) or the hexose monophosphate pathway (HMP). Therefore, the generation of ATP, NADH, and 2,3-DPG (EMP) or NADPH (HMP) shift with RBC O 2 content because of competition between deoxyhemoglobin and key EMP enzymes for binding to the cytoplasmic domain of the Band 3 membrane protein (cdB3). Enzyme inactivation by cdB3 sequestration in oxygenated RBCs favors HMP flux and NADPH generation (maximizing glutathione-based antioxidant systems). We tested the hypothesis that sickle hemoglobin disrupts cdB3-based regulatory protein complex assembly, creating vulnerability to oxidative stress. In RBCs from patients with sickle cell anemia, we demonstrate in the present study constrained HMP flux, NADPH, and glutathione recycling and reduced resilience to oxidative stress manifested by membrane protein oxidation and membrane fragility. Using a novel, inverted membrane-on-bead model, we illustrate abnormal (O 2 -dependent) association of sickle hemoglobin to RBC membrane that interferes with sequestration/inactivation of the EMP enzyme GAPDH. This finding was confirmed by immunofluorescent imaging during RBC O IntroductionSickle cell anemia (SCA) arises from a single amino acid substitution (Glu6Val) in the ␤-globin chain. Although the change to hemoglobin (Hb) is simple and uniform, SCA is characterized by broad differences in clinical manifestation. Phenotype variation in SCA is thought to arise from both environmental and genetic factors (eg, ␤-gene cluster haplotype, degree of HbF expression, or effects of other epistatic genes). The environmental factor that most clearly influences SCA phenotype is hypoxia, which drives sickle Hb (HbS) polymerization and the resulting well-characterized alterations in RBC physiology and the microcirculation. However, the influence of hypoxia on the SCA phenotype appears to be insufficiently explained by HbS polymerization alone. 1 Moreover, we lack a clear mechanistic understanding of the significant oxidative stress complicating SCA, a key feature of phenotype variation, both at rest and in association with hypoxia. 2 Nonpolymerized, solution-phase HbS may promote oxidative stress, even in RBCs under normal physiologic O 2 gradients. 3 Specifically, the low redox potential for heme in HbS 4 and avid binding affinity of HbS for the cytoplasmic regulatory domain of the Band 3 membrane protein (cdB3) 5,6 strongly affect RBC energetics and antioxidant systems [7][8][9] and, notably, do so as a function of RBC O 2 content. Therefore, both the genesis and the disposal of reactive oxygen species are abnormal in SCA, creating a baseline state of oxidative stress, which worsens in hypoxia.In particular, consideration of metabolic control in RBCs suggests O 2 -dependent HbS-cdB3 interaction as a relatively ...

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Nitric Oxide Transport in Blood: A Third Gas in the Respiratory Cycle

Cited by 69 publications

References 317 publications

S-nitrosylation therapy to improve oxygen delivery of banked blood

S-nitrosylation therapy to improve oxygen delivery of banked blood

Upregulation and Mitochondrial Sequestration of Hemoglobin Occur in Circulating Leukocytes during Critical Illness, Conferring a Cytoprotective Phenotype

Sickle hemoglobin disturbs normal coupling among erythrocyte O2 content, glycolysis, and antioxidant capacity

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