Skip to main content

Advertisement

SpringerLink
Log in

Evidence for a metabolic shift of arginine metabolism in sickle cell disease

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Over the last few years, a pivotal role has been ascribed to reduced nitric oxide (NO) availability as a contributing factor to the vaso-occlusive process of sickle cell disease. We investigated whether arginine metabolism in sickle cell patients is different from healthy controls. Blood samples were drawn by venipuncture in the fasting state from 8 clinically asymptomatic HbSS patients and 14 race-matched HbAA controls. HbSS patients had decreased plasma arginine (p=0.001) and increased proline (p=0.015) levels as compared to controls. Ratios of arginine to ornithine (p<0.001), proline (p<0.001), glutamate (p=0.003), and citrulline (p=0.026) were lower in HbSS patients. There were significant correlations of ornithine (rs=−0.71, p=0.047), citrulline (rs=−0.79, p=0.021), arginine/ornithine (rs=0.93, p=0.001), and arginine/citrulline (rs=0.81, p=0.015) to hemoglobin and of arginine/proline (rs=−0.76, p=0.028) and citrulline (rs=0.71, p=0.048) to leukocyte counts. These data indicate that in clinically asymptomatic sickle cell patients increased arginine metabolism is shifted to the arginase pathway and that this seems to be more profound in patients with higher hemolytic rates and leukocyte counts.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2A–F

Similar content being viewed by others

References

  1. Serjeant GR (2001) The emerging understanding of sickle cell disease. Br J Haematol 112:3–18

    Article  CAS  PubMed  Google Scholar 

  2. Frenette PS (2002) Sickle cell vaso-occlusion: multistep and multicellular paradigm. Curr Opin Hematol 9:101–106

    Article  PubMed  Google Scholar 

  3. Francis RB Jr (1991) Platelets, coagulation, and fibrinolysis in sickle cell disease: their possible role in vascular occlusion. Blood Coagul Fibrinolysis 2:341–353

    PubMed  Google Scholar 

  4. Reiter CD, Gladwin MT (2003) An emerging role for nitric oxide in sickle cell disease vascular homeostasis and therapy. Curr Opin Hematol 10:99–107

    Article  CAS  PubMed  Google Scholar 

  5. Schechter AN, Gladwin MT (2003) Hemoglobin and the paracrine and endocrine functions of nitric oxide. N Engl J Med 348:1483–1485

    Article  CAS  PubMed  Google Scholar 

  6. Khan BV, Harrison DG, Olbrych MT, Alexander RW, Medford RM (1996) Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells. Proc Natl Acad Sci U S A 93:9114–9119

    Article  CAS  PubMed  Google Scholar 

  7. Space SL, Lane PA, Pickett CK, Weil JV (2000) Nitric oxide attenuates normal and sickle red blood cell adherence to pulmonary endothelium. Am J Hematol 63:200–204

    Article  CAS  PubMed  Google Scholar 

  8. Belhassen L, Pelle G, Sediame S, Bachir D, Carville C, Bucherer C, Lacombe C, Galacteros F, Adnot S (2001) Endothelial dysfunction in patients with sickle cell disease is related to selective impairment of shear stress-mediated vasodilation. Blood 97:1584–1589

    Article  CAS  PubMed  Google Scholar 

  9. Gladwin MT, Schechter AN, Ognibene FP, Coles WA, Reiter CD, Schenke WH, Csako G, Waclawiw MA, Panza JA, Cannon RO 3rd (2003) Divergent nitric oxide bioavailability in men and women with sickle cell disease. Circulation 107:271–278

    Article  CAS  PubMed  Google Scholar 

  10. Mori M, Gotoh T (2000) Regulation of nitric oxide production by arginine metabolic enzymes. Biochem Biophys Res Commun 275:715–719

    Article  CAS  PubMed  Google Scholar 

  11. Hallemeesch MM, Lamers WH, Deutz NE (2002) Reduced arginine availability and nitric oxide production. Clin Nutr 21:273–279

    Article  CAS  PubMed  Google Scholar 

  12. Morris SM Jr (2002) Regulation of enzymes of the urea cycle and arginine metabolism. Annu Rev Nutr 22:87–105

    Article  CAS  PubMed  Google Scholar 

  13. Van der Dijs FP, van den Berg GA, Schermer JG, Muskiet FD, Landman H, Muskiet FA (1992) Screening cord blood for hemoglobinopathies and thalassemia by HPLC. Clin Chem 38:1864–1869

    PubMed  Google Scholar 

  14. Van der Dijs, Schnog JJ, Brouwer DA, Velvis HJ, van den Berg GA, Bakker AJ, Duits AJ, Muskiet FD, Muskiet FA (1998) Elevated homocysteine levels indicate suboptimal folate status in pediatric sickle cell patients. Am J Hematol 59:192–198

    Article  PubMed  Google Scholar 

  15. Vichinsky E, Kleman K, Embury S, Lubin B (1981) The diagnosis of iron deficiency anemia in sickle cell disease. Blood 58:963–968

    CAS  PubMed  Google Scholar 

  16. Moshage H, Kok B, Huizenga JR, Jansen PL (1995) Nitrite and nitrate determinations in plasma: a critical evaluation. Clin Chem 41:892–896

    CAS  PubMed  Google Scholar 

  17. Reiter CD, Wang X, Tanus-Santos JE, Hogg N, Cannon RO 3rd, Schechter AN, Gladwin MT (2002) Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med 8:1383–1389

    Article  CAS  PubMed  Google Scholar 

  18. Enwonwu CO, Xu XX, Turner E (1990) Nitrogen metabolism in sickle cell anemia: free amino acids in plasma and urine. Am J Med Sci 300:366–371

    CAS  PubMed  Google Scholar 

  19. Lopez BL, Kreshak AA, Morris CR, Davis-Moon L, Ballas SK, Ma XL (2003) L-arginine levels are diminished in adult acute vaso-occlusive sickle cell crisis in the emergency department. Br J Haematol 120:532–534

    Article  CAS  PubMed  Google Scholar 

  20. Van der Jagt DJ, Kanellis GJ, Isichei C, Patuszyn A, Glew RH (1997) Serum and urinary amino acid levels in sickle cell disease. J Trop Pediatr 43:220–225

    PubMed  Google Scholar 

  21. Morris CR, Kuypers FA, Larkin S, Vichinsky EP, Styles LA (2000) Patterns of arginine and nitric oxide in patients with sickle cell disease with vaso-occlusive crisis and acute chest syndrome. J Pediatr Hematol Oncol 22:515–520

    Article  CAS  PubMed  Google Scholar 

  22. Morris CR, Morris SM Jr, Hagar W, Van Warmerdam J, Claster S, Kepka-Lenhart D, Machado L, Kuypers FA, Vichinsky EP (2003) Arginine therapy: a new treatment for pulmonary hypertension in sickle cell disease? Am J Respir Crit Care Med 168:63–69

    Article  PubMed  Google Scholar 

  23. Schnog JB, Lard LR, Rojer RA, van der Dijs FP, Muskiet FA, Duits AJ (1998) New concepts in assessing sickle cell disease severity. Am J Hematol 58:61–66

    Article  CAS  PubMed  Google Scholar 

  24. Li H, Meininger CJ, Hawker JR Jr, Haynes TE, Kepka-Lenhart D, Mistry SK, Morris SM Jr, Wu G (2001) Regulatory role of arginase I and II in nitric oxide, polyamine, and proline syntheses in endothelial cells. Am J Physiol Endocrinol Metab 280:E75-E82

    CAS  PubMed  Google Scholar 

  25. Wagener, Feldman E, de Witte T, Abraham NG (1997) Heme induces the expression of adhesion molecules ICAM-1, VCAM-1, and E selectin in vascular endothelial cells. Proc Soc Exp Biol Med 216:456–463

    CAS  PubMed  Google Scholar 

  26. Schnog JB, Rojer RA, Mac Gillavry MR, ten Cate H, Brandjes DP, Duits AJ (2003) Steady-state sVCAM-1 serum levels in adults with sickle cell disease. Ann Hematol 82:109–113

    CAS  PubMed  Google Scholar 

  27. Serjeant G, Serjeant B, Stephens A, Roper D, Higgs D, Beckford M, Cook J, Thomas P (1996) Determinants of haemoglobin level in steady-state homozygous sickle cell disease. Br J Haematol 92:143–149

    Article  CAS  PubMed  Google Scholar 

  28. Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP (1994) Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 330:1639–1644

    PubMed  Google Scholar 

  29. Lard LR, Mul FP, de Haas M, Roos D, Duits AJ (1999) Neutrophil activation in sickle cell disease. J Leukoc Biol 66:411–415

    CAS  PubMed  Google Scholar 

  30. Cynober LA (2002) Plasma amino acid levels with a note on membrane transport: characteristics, regulation, and metabolic significance. Nutrition 18:761–766

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Internal Medicine (9B), Slotervaart Hospital, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands

    John-John B. Schnog

  2. Red Cross Blood Bank Foundation, Curaçao, Netherlands Antilles

    John-John B. Schnog & Ashley J. Duits

  3. Department of Pathology and Laboratory Medicine, Groningen University Hospital, The Netherlands

    Esther H. Jager & Frits A. J. Muskiet

  4. Analytical Diagnostic Center, Curaçao, Netherlands Antilles

    Esther H. Jager & Fey P. L. van der Dijs

  5. Division of Gastroenterology and Hepatology, Groningen University Hospital, The Netherlands

    Han Moshage

  6. Department of Pediatrics, St. Elisabeth Hospital, Curaçao, Netherlands Antilles

    Fred D. Muskiet

Authors
  1. John-John B. Schnog
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Esther H. Jager
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fey P. L. van der Dijs
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ashley J. Duits
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Han Moshage
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fred D. Muskiet
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Frits A. J. Muskiet
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John-John B. Schnog.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schnog, JJ.B., Jager, E.H., van der Dijs, F.P.L. et al. Evidence for a metabolic shift of arginine metabolism in sickle cell disease. Ann Hematol 83, 371–375 (2004). https://doi.org/10.1007/s00277-004-0856-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-004-0856-9

Keywords

Search

Navigation