Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002895 (sickle cell disease)
 11,747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

S-Nitrosated hemoglobin (SNO-Hb) is of interest because of the allosteric control of NO delivery from SNO-Hb made possible by the conformational differences between the R- and T-states of Hb. To better understand SNO-Hb, the oxygen binding properties of S-nitrosated forms of normal and sickle cell Hb were investigated. Spectral assays and electrospray ionization mass spectrometry were used to quantify the degree of S-nitrosation. Hb A(0) and unpolymerized Hb S exhibit similar shifts toward their R-state conformations in response to S-nitrosation, with increased oxygen affinity and decreased cooperativity. Responses to 2, 3-diphosphoglycerate were unaltered, indicating regional changes in the deoxy structure of SNO-Hb that accommodate NO adduction. A cycle of deoxygenation/reoxygenation does not cause loss of NO or appreciable heme oxidation. There is, however, appreciable loss of NO and heme oxidation when oxygen-binding experiments are carried out in the presence of glutathione. These results indicate that the in vivo stability of SNO-Hb and its associated vasoactivity depend on the abundance of thiols and other factors that influence transnitrosation reactions. The increased oxygen affinity and R-state character that result from S-nitrosation of Hb S would be expected to decrease its polymerization and thereby lessen the associated symptoms of sickle cell disease.
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PMID:Effects of S-nitrosation on oxygen binding by normal and sickle cell hemoglobin. 1045 44

We have recently reported that nitric oxide inhalation in individuals with sickle cell anemia increases the level of NO bound to hemoglobin, with the development of an arterial-venous gradient, suggesting delivery to the tissues. A recent model suggests that nitric oxide, in addition to its well-known reaction with heme groups, reacts with the beta-globin chain cysteine 93 to form S-nitrosohemoglobin (SNO-Hb) and that SNO-Hb would preferentially release nitric oxide in the tissues and thus modulate blood flow. However, we have also recently determined that the primary NO hemoglobin adduct formed during NO breathing in normal (hemoglobin A) individuals is nitrosyl (heme)hemoglobin (HbFeIINO), with only a small amount of SNO-Hb formation. To determine whether the NO is transported as HbFeIINO or SNO-Hb in sickle cell individuals, which would have very different effects on sickle hemoglobin polymerization, we measured these two hemoglobin species in three sickle cell volunteers before and during a dose escalation of inhaled NO (40, 60, and 80 ppm). Similar to our previous observations in normal individuals, the predominant species formed was HbFeIINO, with a significant arterial-venous gradient. Minimal SNO-Hb was formed during NO breathing, a finding inconsistent with significant transport of NO using this pathway, but suggesting that this pathway exists. These results suggest that NO binding to heme groups is physiologically a rapidly reversible process, supporting a revised model of hemoglobin delivery of NO in the peripheral circulation and consistent with the possibility that NO delivery by hemoglobin may be therapeutically useful in sickle cell disease.
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PMID:Nitric oxide transport on sickle cell hemoglobin: where does it bind? 1169 98

Red blood cells (RBCs) have been ascribed a unique role in dilating blood vessels, which requires O2-regulated binding and bioactivation of NO by Hb and transfer of NO equivalents to the RBC membrane. Vasoocclusion in hypoxic tissues is the hallmark of sickle cell anemia. Here we show that sickle cell Hb variant S (HbS) is deficient both in the intramolecular transfer of NO from heme iron (iron nitrosyl, FeNO) to cysteine thiol (S-nitrosothiol, SNO) that subserves bioactivation, and in transfer of the NO moiety from S-nitrosohemoglobin (SNO-HbS) to the RBC membrane. As a result, sickle RBCs are deficient in membrane SNO and impaired in their ability to mediate hypoxic vasodilation. Further, the magnitudes of these impairments correlate with the clinical severity of disease. Thus, our results suggest that abnormal RBC vasoactivity contributes to the vasoocclusive pathophysiology of sickle cell anemia, and that the phenotypic variation in expression of the sickle genotype may be explained, in part, by variable deficiency in RBC processing of NO. More generally, our findings raise the idea that defective NO processing may characterize a new class of hemoglobinopathy.
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PMID:Impaired vasodilation by red blood cells in sickle cell disease. 1569 45

The SNO-Hb hypothesis holds that heme-bound nitric oxide (NO) present in the beta subunits of T-state hemoglobin (Hb) will be transferred to the beta-93 cysteine upon conversion to R-state Hb, thereby forming SNO-Hb. A deficiency in the ability of Hb to facilitate this intramolecular transfer has recently been purported to play a role in pulmonary hypertension and sickle cell disease. We prepared deoxygenated Hb samples with small amounts of heme-bound NO and then oxygenated the samples. Electron paramagnetic resonance (EPR) spectroscopy was used to (1) determine the concentration of iron nitrosyl Hb (Fe-NO Hb), (2) show that the NO is evenly distributed among alpha and beta subunits, and (3) show that the Hb undergoes a change in its quaternary state (T to R) upon oxygenation. We did not observe a decrease in the concentration of Fe-NO Hb on oxygenation, which is inconsistent with the prediction of the SNO-Hb hypothesis.
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PMID:Lack of allosterically controlled intramolecular transfer of nitric oxide from the heme to cysteine in the beta subunit of hemoglobin. 1705 23

The biology of NO (nitric oxide) is poorly explained by the activity of the free radical NO ((.)NO) itself. Although (.)NO acts in an autocrine and paracrine manner, it is also in chemical equilibrium with other NO species that constitute stable stores of NO bioactivity. Among these species, S-nitrosylated hemoglobin (S-nitrosohemoglobin; SNO-Hb) is an evolved transducer of NO bioactivity that acts in a responsive and exquisitely regulated manner to control cardiopulmonary and vascular homeostasis. In SNO-Hb, O(2) sensing is dynamically coupled to formation and release of vasodilating SNOs, endowing the red blood cell (RBC) with the capacity to regulate its own principal function, O(2) delivery, via regulation of blood flow. Analogous, physiological actions of RBC SNO-Hb also contribute to central nervous responses to blood hypoxia, the uptake of O(2) from the lung to blood, and baroreceptor-mediated control of the systemic flow of blood. Dysregulation of the formation, export, or actions of RBC-derived SNOs has been implicated in human diseases including sepsis, sickle cell anemia, pulmonary arterial hypertension, and diabetes mellitus. Delivery of SNOs by the RBC can be harnessed for therapeutic gain, and early results support the logic of this approach in the treatment of diseases as varied as cancer and neonatal pulmonary hypertension.
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PMID:Transport and peripheral bioactivities of nitrogen oxides carried by red blood cell hemoglobin: role in oxygen delivery. 1742 Mar 1