Detection of Mutant Hemoglobins with Altered Affinity for Oxygen

Lichtman, Marshall A.; Murphy, Marion; Adamson, John W.

doi:10.7326/0003-4819-84-5-517

Cited by 58 publications

(28 citation statements)

References 5 publications

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“…Blood PaO 2 and pH were measured by blood gas analyzer, and SaO 2 was measured by Co-Oximeter. The P50 was then calculated by using a Hill constant of 2.7 and the standard equation as described before 26 .…”

Section: Methodsmentioning

confidence: 99%

Beneficial Role of Erythrocyte Adenosine A2B Receptor–Mediated AMP-Activated Protein Kinase Activation in High-Altitude Hypoxia

et al. 2016

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Background High altitude is a challenging condition caused by insufficient oxygen (O2) supply. Inability to adjust to hypoxia may lead to pulmonary edema, stroke, cardiovascular dysfunction and even death. Thus, understanding the molecular basis of adaptation to high altitude may reveal novel therapeutics to counteract the detrimental consequences of hypoxia. Methods Using high throughput unbiased metabolomic profiling, we report that the metabolic pathway responsible for production of erythrocyte 2,3-bisphosphoglycerate (2,3-BPG), a negative allosteric regulator of hemoglobin-O2 binding affinity, was significantly induced in 21 healthy humans within two hours of arrival at 5260m, and further increased following 16 days at 5260m. Results This finding led us to uncover discover that plasma adenosine concentrations and soluble CD73 (sCD73) activity rapidly increased at high altitude and were associated with elevated erythrocyte 2,3-BPG levels and O2 releasing capacity. Mouse genetic studies demonstrated that elevated CD73 contributed to hypoxia-induced adenosine accumulation and that elevated adenosine-mediated erythrocyte A2B adenosine receptor (ADORA2B) activation was beneficial by inducing 2,3-BPG production, triggering O2 release to prevent multiple tissue hypoxia, inflammation and pulmonary vascular leakage. Mechanistically, we demonstrated that erythrocyte AMP-activated protein kinase (AMPK) was activated in humans at high altitude and that AMPK is a key protein functioning downstream of ADORA2B, phosphorylating and activating BPG mutase and in this way inducing 2,3-BPG production and O2 release from erythrocytes. Significantly, preclinical studies demonstrated that activation of AMPK enhanced BPG mutase activation, 2,3-BPG production and O2 release capacity in CD73-deficient mice, in erythrocyte specific ADORA2B knockouts, and in wild type mice and in turn reduced tissue hypoxia, and inflammation. Conclusions Altogether, both human and mouse studies reveal novel mechanisms of hypoxia adaptation and potential therapeutic approaches for counteracting hypoxia-induced tissue damage.

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Section: Methodsmentioning

confidence: 99%

Beneficial Role of Erythrocyte Adenosine A2B Receptor–Mediated AMP-Activated Protein Kinase Activation in High-Altitude Hypoxia

et al. 2016

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“…The resultant curve has a sigmoid shape due to the cooperative binding of oxygen to the four globins in the hemoglobin tetramer, enumerated as Hill coefficient “n”. If a hemoximeter is not available, the P50 can be estimated from the venous blood gas using the measured PO 2 , oxygen percent saturation and pH using a formula described by Lichtman and colleagues 13 ; however, the Hill coefficient “n” cannot be derived by this method.…”

Section: Methodsmentioning

confidence: 99%

“…The PO 2 in venous blood at 37° C was converted to PO 2 at pH 7.4 with the formula:

log {normalP normalO}_{2 false(7.4 false)} = log {normalP normalO}_{2} - false[0.5 false(7.40 - normalp normalH false) false]

where pH is measured from the antecubital venous blood 13 .…”

Section: Methodsmentioning

confidence: 99%

High altitude genetic adaptation in Tibetans: No role of increased hemoglobin–oxygen affinity

Tashi

Tian

Koul

et al. 2014

Blood Cells, Molecules, and Diseases

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High altitude exerts selective evolutionary pressure primarily due to its hypoxic environment, resulting in multiple adaptive responses. High hemoglobin-oxygen affinity is postulated to be one such adaptive change, which has been reported in Sherpas of the Himalayas. Tibetans have lived on the Qinghai-Tibetan plateau for thousands of years and have developed unique phenotypes, such as protection from polycythemia which has been linked to PDH2 mutation, resulting in downregulation of HIF pathway. In order to see if Tibetans also developed high hemoglobin-oxygen affinity as a part of their genetic adaptation, we conducted this study assessing hemoglobin-oxygen affinity and their fetal hemoglobin levels in Tibetan subjects from 3 different altitudes. We found normal hemoglobin-oxygen affinity in all subjects, fetal hemoglobin levels were normal in all except one and no hemoglobin variants in any of the subjects. We conclude that increased hemoglobin-oxygen affinity or increased fetal hemoglobin are not adaptive phenotypes of the Tibetan highlanders.

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“…P50 was calculated using Litchman equation from PO 2 , SO 2 and pH values of venous blood (9) .We observed no change in P50 values upon high altitude exposure in these two populations. Though the P50 values are well within normal range (22-28mmHg), but as compared to Indians, Kyrgyz had a higher mean P50 as compared to Indians representing a higher oxygen delivery.…”

Section: Discussionmentioning

confidence: 57%

"Analysis of Haemoglobin Variants and Oxygen Affinity in Indian and Kyrgyz Population Groups"

2017

IJCRR

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Aim:The hemoglobin (Hb) variants can alter the structure and biochemical functions of Hb along with affecting physiological properties of the individual. In normal adult RBC, Hb variants that exist are HbA1, HbA2, HbS and HbF. Mutations in globin chains can change the Hb-O 2 affinity which can alter the normal loading of oxygen in lungs and unloading in the tissues and also affect arterial oxygen saturation. Absence of abnormal Hbs rules out upto some extent presence of genetic or acquired facilitated oxygen affinity. Methodology:The study was undertaken to compare haemoglobin variants using HPLC in Indians (n=10) and Kyrgyz population groups (n=10). We estimated oxygen affinity (P50) from PO 2 , SO 2 and pH values using Lichtman equation and peripheral oxygen saturation (SpO 2 ) using pulse oximetry at basal and upon acute HA exposure to 4111m in both the population groups. Results:We obtained Hb fractions A1a, A1b, A1c and A2 within normal range and no HbF or HbS fractions were found in any volunteer from HPLC run. All the P50 values were well within normal range . No change in P50 was observed upon HA exposure in these two populations but Kyrgyz have been found to have a higher P50 compared to Indians at basal. Discussion and Conclusion:Since our data rule-out the existence of abnormal Hb variant in either of the population, thus the significant decrease in SpO 2 observed upon HA induction in both the groups is due to hypoxia at HA and higher P50 in Kyrgyz compared to Indians is population specific.

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Detection of Mutant Hemoglobins with Altered Affinity for Oxygen

Cited by 58 publications

References 5 publications

Beneficial Role of Erythrocyte Adenosine A2B Receptor–Mediated AMP-Activated Protein Kinase Activation in High-Altitude Hypoxia

Beneficial Role of Erythrocyte Adenosine A2B Receptor–Mediated AMP-Activated Protein Kinase Activation in High-Altitude Hypoxia

High altitude genetic adaptation in Tibetans: No role of increased hemoglobin–oxygen affinity

"Analysis of Haemoglobin Variants and Oxygen Affinity in Indian and Kyrgyz Population Groups"

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