AltitudeOmics: Red Blood Cell Metabolic Adaptation to High Altitude Hypoxia

Journal of Proteome Research

Volumn 15, Issue 10, 2016, Pages 3883-3895

  D'Alessandro, Angelo ^a   Nemkov, Travis ^a   Sun, Kaiqi ^b   Liu, Hong ^b   Song, Anren ^b   Monte, Andrew A ^c   Subudhi, Andrew W ^c,d   Lovering, Andrew T ^e   Dvorkin, Daniel ^c   Julian, Colleen G ^c   Kevil, Christopher G ^f   Kolluru, Gopi K ^f   Shiva, Sruti ^g   Gladwin, Mark T ^g   Xia, Yang ^b   Hansen, Kirk C ^a   Roach, Robert C ^c  

^a UNIVERSITY OF COLORADO SCHOOL OF MEDICINE   (United States)

^b UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

^c UNIVERSITY OF COLORADO   (United States)

^d UNIVERSITY OF COLORADO   (United States)

^e UNIVERSITY OF OREGON   (United States)

^f LOUISIANA STATE UNIVERSITY   (United States)

^g UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

Author keywords

hydrogen sulfide; mass spectrometry; metabolic linkage; metabolomics; nitric oxide; red blood cell

Indexed keywords

2,3 DIPHOSPHOGLYCERIC ACID; ADENOSINE PHOSPHATE; ARGININE; CREATINE; CREATINE PHOSPHATE; CREATININE; CYSTEINE; DEOXYHEMOGLOBIN; GLUTATHIONE; HEMOGLOBIN; HYDROGEN SULFIDE; NITRATE; NITRIC OXIDE; NITRITE; OXYGEN; PURINE; SULFUR; UREA; PURINE DERIVATIVE;

ACIDIFICATION; ADULT; ALTITUDE ACCLIMATIZATION; ALTITUDE DISEASE; ARTICLE; BOHR EFFECT; CATABOLISM; CLINICAL ARTICLE; CONTROLLED STUDY; CYTOSOL; DEOXYGENATION; ENDOTHELIUM CELL; ENERGY METABOLISM; ERYTHROCYTE; EVOLUTIONARY ADAPTATION; FEMALE; HUMAN; HUMAN CELL; MALE; MASS SPECTROMETRY; METABOLITE; METABOLOMICS; NITROGEN METABOLISM; OXIDATIVE STRESS; PENTOSE PHOSPHATE CYCLE; PRIORITY JOURNAL; PROTEIN HOMEOSTASIS; PURINE METABOLISM; RETENTION TIME; TRANSAMINATION; ULTRA PERFORMANCE LIQUID CHROMATOGRAPHY; UREA CYCLE; YOUNG ADULT; ACCLIMATIZATION; ADAPTATION; ALTITUDE; GLYCOLYSIS; METABOLISM; NORMAL HUMAN; PATHOPHYSIOLOGY; PHYSIOLOGY; TIME FACTOR;

ACCLIMATIZATION; ADAPTATION, PHYSIOLOGICAL; ADULT; ALTITUDE; ALTITUDE SICKNESS; ARGININE; ERYTHROCYTES; GLUTATHIONE; GLYCOLYSIS; HEALTHY VOLUNTEERS; HUMANS; PENTOSE PHOSPHATE PATHWAY; PURINES; SULFUR; TIME FACTORS; YOUNG ADULT;

EID: 84990841758     PISSN: 15353893     EISSN: 15353907     Source Type: Journal    
DOI: 10.1021/acs.jproteome.6b00733     Document Type: Article

References (78)

1. Semenza, G. L. Hypoxia-Inducible Factor 1 and Cardiovascular Disease Annu. Rev. Physiol. 2014, 76 (1) 39-56 10.1146/annurev-physiol-021113-170322
2. Stenmark, K. R.; Fagan, K. A.; Frid, M. G. Hypoxia-Induced Pulmonary Vascular Remodeling Cellular and Molecular Mechanisms Circ. Res. 2006, 99 (7) 675-691 10.1161/01.RES.0000243584.45145.3f
3. D'Alessandro, A.; Kriebardis, A. G.; Rinalducci, S.; Antonelou, M. H.; Hansen, K. C.; Papassideri, I. S.; Zolla, L. An update on red blood cell storage lesions, as gleaned through biochemistry and omics technologies Transfusion 2015, 55 (1) 205-219 10.1111/trf.12804
4. Peltz, E.; D'Alessandro, A.; Moore, E.; Chin, T.; Silliman, C.; Sauaia, A.; Hansen, K.; Banerjee, A. Pathologic metabolism: An exploratory study of the plasma metabolome of critical injury J. Trauma Acute Care Surg. 2015, 78 (4) 742-51 10.1097/TA.0000000000000589
5. Drew, K. L.; Harris, M. B.; LaManna, J. C.; Smith, M. A.; Zhu, X. W.; Ma, Y. L. Hypoxia tolerance in mammalian heterotherms J. Exp. Biol. 2004, 207 (18) 3155-3162 10.1242/jeb.01114
6. Carey, H. V.; Andrews, M. T.; Martin, S. L. Mammalian hibernation: cellular and molecular responses to depressed metabolism and low temperature Physiol. Rev. 2003, 83 (4) 1153-1181 10.1152/physrev.00008.2003
7. Moore, L. G. Human genetic adaptation to high altitude High Alt. Med. Biol. 2001, 2 (2) 257-279 10.1089/152702901750265341
8. Duhm, J.; Gerlach, E. On the mechanisms of the hypoxia-induced increase of 2,3-diphosphoglycerate in erythrocytes Pfluegers Arch. 1971, 326 (3) 254-269 10.1007/BF00592506
9. Fencl, V.; Gabel, R. A.; Wolfe, D. Composition of cerebral fluids in goats adapted to high altitude J. Appl. Physiol. 1979, 47 (3) 508-513
10. Wood, S. C. Adaptation of Red Blood Cell Function to Hypoxia and Temperature in Ectothermic Vertebrates Am. Zool. 1980, 20 (1) 163-172 10.1093/icb/20.1.163
11. Samaja, M.; Brenna, L.; Allibardi, S.; Cerretelli, P. Human red blood cell aging at 5,050-m altitude: a role during adaptation to hypoxia J. Appl. Physiol. 1993, 75 (4) 1696-1701
12. Savourey, G.; Garcia, N.; Besnard, Y.; Hanniquet, A.-M.; Fine, M.-O.; Bittel, J. Physiological changes induced by pre-adaptation to high altitude Eur. J. Appl. Physiol. Occup. Physiol. 1994, 69 (3) 221-227 10.1007/BF01094792
13. Savourey, G.; Garcia, N.; Caravel, J. P.; Gharib, C.; Pouzeratte, N.; Martin, S.; Bittel, J. Pre-adaptation, adaptation and de-adaptation to high altitude in humans: hormonal and biochemical changes at sea level Eur. J. Appl. Physiol. 1997, 77 (1-2) 37-43 10.1007/s004210050297
14. Hornbein, T.; Schoene, R. High Altitude: An Exploration of Human Adaptation; CRC Press: Washington, DC, 2001; pp 1-986.
15. Ryan, B. J.; Wachsmuth, N. B.; Schmidt, W. F.; Byrnes, W. C.; Julian, C. G.; Lovering, A. T.; Subudhi, A. W.; Roach, R. C. AltitudeOmics: Rapid Hemoglobin Mass Alterations with Early Acclimatization to and De-Acclimatization from 5260 m in Healthy Humans PLoS One 2014, 9 (10) e108788 10.1371/journal.pone.0108788
16. Eckardt, K. U.; Boutellier, U.; Kurtz, A.; Schopen, M.; Koller, E. A.; Bauer, C. Rate of erythropoietin formation in humans in response to acute hypobaric hypoxia J. Appl. Physiol. 1989, 66 (4) 1785-1788
17. Faura, J.; Ramos, J.; Reynafarje, C.; English, E.; Finne, P.; Finch, C. A. Effect of altitude on erythropoiesis Blood 1969, 33 (5) 668-676
18. Wenger, R. H. Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression FASEB J. 2002, 16 (10) 1151-1162 10.1096/fj.01-0944rev
19. Semenza, G. L. Regulation of Metabolism by Hypoxia-Inducible Factor 1 Cold Spring Harbor Symp. Quant. Biol. 2011, 76, 347-353 10.1101/sqb.2011.76.010678
20. Ball, M. K.; Waypa, G. B.; Mungai, P. T.; Nielsen, J. M.; Czech, L.; Dudley, V. J.; Beussink, L.; Dettman, R. W.; Berkelhamer, S. K.; Steinhorn, R. H. et al. Regulation of hypoxia-induced pulmonary hypertension by vascular smooth muscle hypoxia-inducible factor-1α Am. J. Respir. Crit. Care Med. 2014, 189 (3) 314-324 10.1164/rccm.201302-0302OC
21. Lorenzo, F. R.; Huff, C.; Myllymäki, M.; Olenchock, B.; Swierczek, S.; Tashi, T.; Gordeuk, V.; Wuren, T.; Ri-Li, G.; McClain, D. A. et al. A genetic mechanism for Tibetan high-altitude adaptation Nat. Genet. 2014, 46 (9) 951-956 10.1038/ng.3067
22. Marín-Hernández, A.; Gallardo-Pérez, J. C.; Ralph, S. J.; Rodríguez-Enríquez, S.; Moreno-Sánchez, R. HIF-1alpha modulates energy metabolism in cancer cells by inducing over-expression of specific glycolytic isoforms Mini-Rev. Med. Chem. 2009, 9 (9) 1084-1101 10.2174/138955709788922610
23. Tennant, D. A.; Frezza, C.; MacKenzie, E. D.; Nguyen, Q. D.; Zheng, L.; Selak, M. A.; Roberts, D. L.; Dive, C.; Watson, D. G.; Aboagye, E. O. et al. Reactivating HIF prolyl hydroxylases under hypoxia results in metabolic catastrophe and cell death Oncogene 2009, 28 (45) 4009-4021 10.1038/onc.2009.250
24. Monod, J.; Wyman, J.; Changeux, J.-P. On the nature of allosteric transitions: A plausible model J. Mol. Biol. 1965, 12 (1) 88-118 10.1016/S0022-2836(65)80285-6
25. D'Alessandro, A.; Zolla, L. Biochemistry of red cell aging in vivo and storage lesion Haematologica 2013, 98 (1) 398-396
26. Castagnola, M.; Messana, I.; Sanna, M. T.; Giardina, B. Oxygen-linked modulation of erythrocyte metabolism: state of the art Blood Transfus. 2010, 8 (Suppl. 3) s53-s58
27. Low, P. S.; Rathinavelu, P.; Harrison, M. L. Regulation of glycolysis via reversible enzyme binding to the membrane protein, band 3 J. Biol. Chem. 1993, 268 (20) 14627-14631
28. Giardina, B.; Messana, I.; Scatena, R.; Castagnola, M. The Multiple Functions of Hemoglobin Crit. Rev. Biochem. Mol. Biol. 1995, 30 (3) 165-196 10.3109/10409239509085142
29. Messana, I.; Orlando, M.; Cassiano, L.; Pennacchietti, L.; Zuppi, C.; Castagnola, M.; Giardina, B. Human erythrocyte metabolism is modulated by the O2-linked transition of hemoglobin FEBS Lett. 1996, 390 (1) 25-28 10.1016/0014-5793(96)00624-2
30. Rogers, S. C.; Said, A.; Corcuera, D.; McLaughlin, D.; Kell, P.; Doctor, A. Hypoxia limits antioxidant capacity in red blood cells by altering glycolytic pathway dominance FASEB J. 2009, 23 (9) 3159-3170 10.1096/fj.09-130666
31. Yachie-Kinoshita, A.; Nishino, T.; Shimo, H.; Suematsu, M.; Tomita, M. A metabolic model of human erythrocytes: practical application of the E-Cell Simulation Environment J. Biomed. Biotechnol. 2010, 10.1155/2010/642420
32. D'Alessandro, A.; Gevi, F.; Zolla, L. Red blood cell metabolism under prolonged anaerobic storage Mol. BioSyst. 2013, 9 (6) 1196-1209 10.1039/c3mb25575a
33. Subudhi, A. W.; Bourdillon, N.; Bucher, J.; Davis, C.; Elliott, J. E.; Eutermoster, M.; Evero, O.; Fan, J.-L.; Jameson-Van Houten, S.; Julian, C. G. et al. AltitudeOmics: the integrative physiology of human acclimatization to hypobaric hypoxia and its retention upon reascent PLoS One 2014, 9 (3) e92191 10.1371/journal.pone.0092191
34. Amann, M.; Goodall, S.; Twomey, R.; Subudhi, A. W.; Lovering, A. T.; Roach, R. C. AltitudeOmics: on the consequences of high-altitude acclimatization for the development of fatigue during locomotor exercise in humans J. Appl. Physiol. 2013, 115 (5) 634-642 10.1152/japplphysiol.00606.2013
35. Fan, J.-L.; Subudhi, A. W.; Evero, O.; Bourdillon, N.; Kayser, B.; Lovering, A. T.; Roach, R. C. AltitudeOmics: enhanced cerebrovascular reactivity and ventilatory response to CO2 with high-altitude acclimatization and reexposure J. Appl. Physiol. 2014, 116 (7) 911-918 10.1152/japplphysiol.00704.2013
36. Goodall, S.; Twomey, R.; Amann, M.; Ross, E. Z.; Lovering, A. T.; Romer, L. M.; Subudhi, A. W.; Roach, R. C. AltitudeOmics: exercise-induced supraspinal fatigue is attenuated in healthy humans after acclimatization to high altitude Acta Physiol. 2014, 210 (4) 875-888 10.1111/apha.12241
37. Roach, E. B.; Bleiberg, J.; Lathan, C. E.; Wolpert, L.; Tsao, J. W.; Roach, R. C. AltitudeOmics: Decreased reaction time after high altitude cognitive testing is a sensitive metric of hypoxic impairment NeuroReport 2014, 25, 814 10.1097/WNR.0000000000000169
38. Subudhi, A. W.; Fan, J.-L.; Evero, O.; Bourdillon, N.; Kayser, B.; Julian, C. G.; Lovering, A. T.; Panerai, R. B.; Roach, R. C. AltitudeOmics: cerebral autoregulation during ascent, acclimatization, and re-exposure to high altitude and its relation with acute mountain sickness J. Appl. Physiol. 2014, 116 (7) 724-729 10.1152/japplphysiol.00880.2013
39. Subudhi, A. W.; Fan, J.-L.; Evero, O.; Bourdillon, N.; Kayser, B.; Julian, C. G.; Lovering, A. T.; Roach, R. C. AltitudeOmics: effect of ascent and acclimatization to 5260 m on regional cerebral oxygen delivery Exp. Physiol. 2014, 99 (5) 772-781 10.1113/expphysiol.2013.075184
40. D'Alessandro, A.; Nemkov, T.; Kelher, M.; West, F. B.; Schwindt, R. K.; Banerjee, A.; Moore, E. E.; Silliman, C. C.; Hansen, K. C. Routine storage of red blood cell (RBC) units in additive solution-3: a comprehensive investigation of the RBC metabolome Transfusion 2015, 55 (6) 1155-68 10.1111/trf.12975
41. D'Alessandro, A.; Nemkov, T.; Hansen, K. C.; Szczepiorkowski, Z. M.; Dumont, L. J. Red blood cell storage in additive solution-7 preserves energy and redox metabolism: a metabolomics approach Transfusion 2015, 55 (12) 2955-2966 10.1111/trf.13253
42. Clasquin, M. F.; Melamud, E.; Rabinowitz, J. D. LC-MS data processing with MAVEN: a metabolomic analysis and visualization engine Curr. Protoc. Bioinf. 2012, 10.1002/0471250953.bi1411s37
43. Gladwin, M. T.; Shelhamer, J. H.; Schechter, A. N.; Pease-Fye, M. E.; Waclawiw, M. A.; Panza, J. A.; Ognibene, F. P.; Cannon, R. O. Role of circulating nitrite and S-nitrosohemoglobin in the regulation of regional blood flow in humans Proc. Natl. Acad. Sci. U. S. A. 2000, 97 (21) 11482-11487 10.1073/pnas.97.21.11482
44. Peter, E. A.; Shen, X.; Shah, S. H.; Pardue, S.; Glawe, J. D.; Zhang, W. W.; Reddy, P.; Akkus, N. I.; Varma, J.; Kevil, C. G. Plasma Free H2S Levels are Elevated in Patients With Cardiovascular Disease J. Am. Heart Assoc. 2013, 2 (5) e000387 10.1161/JAHA.113.000387
45. Darghouth, D.; Koehl, B.; Junot, C.; Roméo, P.-H. Metabolomic analysis of normal and sickle cell erythrocytes Transfus. Clin. Biol. J. Société Fr. Transfus. Sang. 2010, 17 (3) 148-150 10.1016/j.tracli.2010.06.011
46. Sana, T. R.; Gordon, D. B.; Fischer, S. M.; Tichy, S. E.; Kitagawa, N.; Lai, C.; Gosnell, W. L.; Chang, S. P. Global mass spectrometry based metabolomics profiling of erythrocytes infected with Plasmodium falciparum PLoS One 2013, 8 (4) e60840 10.1371/journal.pone.0060840
47. Ramírez-Zamora, S.; Méndez-Rodríguez, M. L.; Olguín-Martínez, M.; Sánchez-Sevilla, L.; Quintana-Quintana, M.; García-García, N.; Hernández-Muñoz, R. Increased erythrocytes by-products of arginine catabolism are associated with hyperglycemia and could be involved in the pathogenesis of type 2 diabetes mellitus PLoS One 2013, 8 (6) e66823 10.1371/journal.pone.0066823
48. Kleinbongard, P.; Schulz, R.; Rassaf, T.; Lauer, T.; Dejam, A.; Jax, T.; Kumara, I.; Gharini, P.; Kabanova, S.; Ozüyaman, B. et al. Red blood cells express a functional endothelial nitric oxide synthase Blood 2006, 107 (7) 2943-2951 10.1182/blood-2005-10-3992
49. Yang, J.; Gonon, A. T.; Sjöquist, P.-O.; Lundberg, J. O.; Pernow, J. Arginase regulates red blood cell nitric oxide synthase and export of cardioprotective nitric oxide bioactivity Proc. Natl. Acad. Sci. U. S. A. 2013, 110 (37) 15049-15054 10.1073/pnas.1307058110
50. Krotova, K.; Patel, J. M.; Block, E. R.; Zharikov, S. Hypoxic upregulation of arginase II in human lung endothelial cells Am. J. Physiol. Cell Physiol. 2010, 299 (6) C1541-C1548 10.1152/ajpcell.00068.2010
51. Wagner, C. A. Hydrogen sulfide: a new gaseous signal molecule and blood pressure regulator J. Nephrol. 2009, 22 (2) 173-176
52. Kovalevsky, A.; Chatake, T.; Shibayama, N.; Park, S.-Y.; Ishikawa, T.; Mustyakimov, M.; Fisher, S. Z.; Langan, P.; Morimoto, Y. Protonation states of histidine and other key residues in deoxy normal human adult hemoglobin by neutron protein crystallography Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66 (11) 1144-1152 10.1107/S0907444910025448
53. Darghouth, D.; Koehl, B.; Heilier, J. F.; Madalinski, G.; Bovee, P.; Bosman, G.; Delaunay, J.; Junot, C.; Roméo, P.-H. Alterations of red blood cell metabolome in overhydrated hereditary stomatocytosis Haematologica 2011, 96 (12) 1861-1865 10.3324/haematol.2011.045179
54. D'Alessandro, A.; D'Amici, G. M.; Vaglio, S.; Zolla, L. Time-course investigation of SAGM-stored leukocyte-filtered red bood cell concentrates: from metabolism to proteomics Haematologica 2012, 97 (1) 107-115 10.3324/haematol.2011.051789
55. D'Amici, G. M.; Mirasole, C.; D'Alessandro, A.; Yoshida, T.; Dumont, L. J.; Zolla, L. Red blood cell storage in SAGM and AS3: a comparison through the membrane two-dimensional electrophoresis proteome Blood Transfus. 2012, 10 (Suppl. 2) s46-s54
56. D'Alessandro, A.; Hansen, K. C.; Silliman, C. C.; Moore, E. E.; Kelher, M.; Banerjee, A. Metabolomics of AS-5 RBC supernatants following routine storage Vox Sang. 2015, 108 (2) 131-40 10.1111/vox.12193
57. Dosek, A.; Ohno, H.; Acs, Z.; Taylor, A. W.; Radak, Z. High altitude and oxidative stress Respir. Physiol. Neurobiol. 2007, 158 (2-3) 128-131 10.1016/j.resp.2007.03.013
58. Raftos, J. E.; Whillier, S.; Kuchel, P. W. Glutathione Synthesis and Turnover in the Human Erythrocyte Alignment of a model based on detailed enzyme kinetics with experimental data J. Biol. Chem. 2010, 285 (31) 23557-23567 10.1074/jbc.M109.067017
59. Reisz, J. A.; Wither, M. J.; Dzieciatkowska, M.; Nemkov, T.; Issaian, A.; Yoshida, T.; Dunham, A. J.; Hill, R. C.; Hansen, K. C.; D'Alessandro, A. Oxidative modifications of glyceraldehyde 3-phosphate dehydrogenase regulate metabolic reprogramming of stored red blood cells Blood 2016, 10.1182/blood-2016-05-714816
60. Sato, A.; Terata, K.; Miura, H.; Toyama, K.; Loberiza, F. R., Jr.; Hatoum, O. A.; Saito, T.; Sakuma, I.; Gutterman, D. D. Mechanism of vasodilation to adenosine in coronary arterioles from patients with heart disease Am. J. Physiol. 2005, 288 (4) H1633-H1640 10.1152/ajpheart.00575.2004
61. Costa, F.; Biaggioni, I. Role of Nitric Oxide in Adenosine-Induced Vasodilation in Humans Hypertension 1998, 31 (5) 1061-1064 10.1161/01.HYP.31.5.1061
62. Zhang, Y.; Dai, Y.; Wen, J.; Zhang, W.; Grenz, A.; Sun, H.; Tao, L.; Lu, G.; Alexander, D. C.; Milburn, M. V. et al. Detrimental effects of adenosine signaling in sickle cell disease Nat. Med. 2011, 17 (1) 79-86 10.1038/nm.2280
63. Liu, H.; Zhang, Y.; Wu, H.; D'Alessandro, A.; Yegutkin, G. G.; Song, A.; Sun, K.; Li, J.; Cheng, N.-Y.; Huang, A. et al. Beneficial Role of Erythrocyte Adenosine A2B Receptor-Mediated AMP-Activated Protein Kinase Activation in High-Altitude HypoxiaClinical Perspective Circulation 2016, 134 (5) 405-421 10.1161/CIRCULATIONAHA.116.021311
64. Saito, D.; Mima, T.; Obayashi, N.; Uchida, S.; Maekawa, K.; Sato, T.; Mizuo, K.; Kobayashi, H.; Haraoka, S. Effects of inosine on adenosine-induced coronary vasodilation in the open chest dog Arzneimittelforschung 1993, 43 (9) 950-953
65. Liu, C.; Wajih, N.; Liu, X.; Basu, S.; Janes, J.; Marvel, M.; Keggi, C.; Helms, C. C.; Lee, A. N.; Belanger, A. M. et al. Mechanisms of human erythrocytic bioactivation of nitrite J. Biol. Chem. 2015, 290 (2) 1281-1294 10.1074/jbc.M114.609222
66. Hackett, P. H. Caffeine at high altitude: java at base cAMP High Alt. Med. Biol. 2010, 11 (1) 13-17 10.1089/ham.2009.1077
67. Billecke, S. S.; Kitzmiller, L. A.; Northrup, J. J.; Whitesall, S. E.; Kimoto, M.; Hinz, A. V.; D'Alecy, L. G. Contribution of whole blood to the control of plasma asymmetrical dimethylarginine Am. J. Physiol. 2006, 291 (4) H1788-H1796 10.1152/ajpheart.00066.2006
68. Lundberg, J. O.; Weitzberg, E.; Gladwin, M. T. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics Nat. Rev. Drug Discovery 2008, 7 (2) 156-167 10.1038/nrd2466
69. Cosby, K.; Partovi, K. S.; Crawford, J. H.; Patel, R. P.; Reiter, C. D.; Martyr, S.; Yang, B. K.; Waclawiw, M. A.; Zalos, G.; Xu, X. et al. Nitrite reduction to nitric oxide by deoxyhemoglobin vasodilates the human circulation Nat. Med. 2003, 9 (12) 1498-1505 10.1038/nm954
70. Akrawinthawong, K.; Park, J. W.; Piknova, B.; Sibmooh, N.; Fucharoen, S.; Schechter, A. N. A flow cytometric analysis of the inhibition of platelet reactivity due to nitrite reduction by deoxygenated erythrocytes PLoS One 2014, 9 (3) e92435 10.1371/journal.pone.0092435
71. Velmurugan, S.; Kapil, V.; Ghosh, S. M.; Davies, S.; McKnight, A.; Aboud, Z.; Khambata, R. S.; Webb, A. J.; Poole, A.; Ahluwalia, A. Antiplatelet effects of dietary nitrate in healthy volunteers: involvement of cGMP and influence of sex Free Radical Biol. Med. 2013, 65, 1521-1532 10.1016/j.freeradbiomed.2013.06.031
72. Park, J. W.; Piknova, B.; Huang, P. L.; Noguchi, C. T.; Schechter, A. N. Effect of blood nitrite and nitrate levels on murine platelet function PLoS One 2013, 8 (2) e55699 10.1371/journal.pone.0055699
73. Corti, P.; Tejero, J.; Gladwin, M. T. Evidence mounts that red cells and deoxyhemoglobin can reduce nitrite to bioactive NO to mediate intravascular endocrine NO signaling: commentary on "Anti-platelet effects of dietary nitrate in healthy volunteers: involvement of cGMP and influence of sex. Free Radical Biol. Med. 2013, 65, 1518-1520 10.1016/j.freeradbiomed.2013.09.020
74. Gladwin, M. T.; Wang, X.; Reiter, C. D.; Yang, B. K.; Vivas, E. X.; Bonaventura, C.; Schechter, A. N. S-Nitrosohemoglobin is unstable in the reductive erythrocyte environment and lacks O2/NO-linked allosteric function J. Biol. Chem. 2002, 277 (31) 27818-27828 10.1074/jbc.M203236200
75. Adcock, K. H.; Nedelcu, J.; Loenneker, T.; Martin, E.; Wallimann, T.; Wagner, B. P. Neuroprotection of creatine supplementation in neonatal rats with transient cerebral hypoxia-ischemia Dev. Neurosci. 2002, 24 (5) 382-388 10.1159/000069043
76. Kai, S.; Tanaka, T.; Daijo, H.; Harada, H.; Kishimoto, S.; Suzuki, K.; Takabuchi, S.; Takenaga, K.; Fukuda, K.; Hirota, K. Hydrogen sulfide inhibits hypoxia- but not anoxia-induced hypoxia-inducible factor 1 activation in a von hippel-lindau- and mitochondria-dependent manner Antioxid. Redox Signaling 2012, 16 (3) 203-216 10.1089/ars.2011.3882
77. Cuvillier, O.; Ader, I. Hypoxia-inducible factors and sphingosine 1-phosphate signaling Anti-Cancer Agents Med. Chem. 2011, 11 (9) 854-862 10.2174/187152011797655050
78. Sun, K.; Zhang, Y.; D'Alessandro, A.; Nemkov, T.; Song, A.; Wu, H.; Liu, H.; Adebiyi, M.; Huang, A.; Wen, Y. E. et al. Sphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia Nat. Commun. 2016, 7, 12086 10.1038/ncomms12086