Depleted nitric oxide and prostaglandin E2 levels are correlated with endothelial dysfunction in β-thalassemia/HbE patients

Abstract

Mechanisms of vascular disorders in β-thalassemia/HbE patients remain poorly understood. In the present study, we aimed to determine the presence of endothelial dysfunction and its association with altered vascular mediators in this population. Forty-three β-thalassemia/HbE patients without clinically documented vascular symptoms and 43 age–sex-matched healthy controls were enrolled. Endothelial function was assessed using flow-mediated dilatation (FMD) before and after administration of nitroglycerine (NTG). β-Thalassemia/HbE patients showed a significant endothelial dysfunction using FMD. The percentage change in the brachial artery diameter before NTG was significantly lower in the thalassemia group compared to the control (5.0 ± 5.9 vs. 9.0 ± 4.0%, p < 0.01) while no significant differences after NTG (18.4 ± 8.3 vs. 17.8 ± 6.3%, p = 0.71). Plasma nitric oxide metabolites (NO x ) and prostaglandin E2 (PGE2) levels were significantly decreased in β-thalassemia/HbE (117.2 ± 27.3 vs. 135.8 ± 11.3 µmol/L, p < 0.01) and (701.9 ± 676.0 vs. 1374.7 ± 716.5 pg/mL, p < 0.01), respectively, while a significant elevation in soluble thrombomodulin levels in β-thalassemia/HbE (3587.7 ± 1310.0 vs. 3093.9 ± 583.8 pg/mL, p = 0.028). NO x and PGE2 levels were significantly correlated with FMD (r = 0.27, p = 0.025) and (r = 0.35, p = 0.003), respectively. These findings suggest roles for endothelial mediators and a new mechanism underlying endothelial dysfunction in β-thalassemia/HbE patients.

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References

  1. 1.

    Vita JA, Keaney JF. Endothelial function: a barometer for cardiovascular risk? Circulation. 2002;106:640–2.

    Article  PubMed  Google Scholar 

  2. 2.

    Hadi HA, Carr CS, Al Suwaidi J. Endothelial dysfunction: cardiovascular risk factors, therapy, and outcome. Vasc Health Risk Manag. 2005;1:183–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007;115:1285–95.

    PubMed  Google Scholar 

  4. 4.

    Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373–6.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Barbato JE, Tzeng E. Nitric oxide and arterial disease. J Vasc Surg. 2004;40:187–93.

    Article  PubMed  Google Scholar 

  6. 6.

    Tousoulis D, Kampoli AM, Tentolouris C, Papageorgiou N, Stefanadis C. The role of nitric oxide on endothelial function. Curr Vasc Pharmacol. 2012;10:4–18.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Sorensen KE, Celermajer DS, Spiegelhalter DJ, Georgakopoulos D, Robinson J, Thomas O, et al. Non-invasive measurement of human endothelium dependent arterial responses: accuracy and reproducibility. Br Heart J. 1995;74:247–53.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, et al. International Brachial Artery Reactivity Task Force: guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002;39:257–65.

    Article  PubMed  Google Scholar 

  9. 9.

    Harris RA, Nishiyama SK, Wray DW, Richardson RS. Ultrasound assessment of flow-mediated dilation. Hypertension. 2010;55:1075–85.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Vichinsky E. Hemoglobin E syndromes. Hematology Am Soc Hematol Educ Program. 2007:79–83. doi:10.1182/asheducation-2007.1.79.

  11. 11.

    Aessopos A, Kati M, Farmakis D. Heart disease in thalassemia intermedia: a review of the underlying pathophysiology. Haematologica. 2007;92:658–65.

    Article  PubMed  Google Scholar 

  12. 12.

    Atichartakarn V, Chuncharunee S, Archararit N, Udomsubpayakul U, Lee R, Tunhasiriwet A, et al. Prevalence and risk factors for pulmonary hypertension in patients with hemoglobin E/β-thalassemia disease. Eur J Haematol. 2014;92:346–53.

    Article  PubMed  Google Scholar 

  13. 13.

    Cheung YF, Chan GC, Ha SY. Arterial stiffness and endothelial function in patients with beta-thalassemia major. Circulation. 2002;106:2561–6.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Aggeli C, Antoniades C, Cosma C, Chrysohoou C, Tousoulis D, Ladis V, et al. Endothelial dysfunction and inflammatory process in transfusion-dependent patients with beta-thalassemia major. Int J Cardiol. 2005;105:80–4.

    Article  PubMed  Google Scholar 

  15. 15.

    Stakos DA, Tavridou A, Margaritis D, Tziakas DN, Kotsianidis I, Chalikias GK, et al. Oxidised low-density lipoprotein and arterial function in beta-thalassemia major. Eur J Haematol. 2009;82:477–83.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Kukongviriyapan V, Somparn N, Senggunprai L, Prawan A, Kukongviriyapan U, Jetsrisuparb A. Endothelial dysfunction and oxidant status in pediatric patients with hemoglobin E-beta thalassemia. Pediatr Cardiol. 2008;29:130–5.

    Article  PubMed  Google Scholar 

  17. 17.

    Aphinives C, Kukongviriyapan U, Jetsrisuparb A, Kukongviriyapan V, Somparn N. Impaired endothelial function in pediatric hemoglobin E/β-thalassemia patients with iron overload. Southeast Asian J Trop Med Public Health. 2014;45:1454–63.

    PubMed  Google Scholar 

  18. 18.

    Butthep P, Rummavas S, Wisedpanichkij R, Jindadamrongwech S, Fucharoen S, Bunyaratvej A. Increased circulating activated endothelial cells, vascular endothelial growth factor, and tumor necrosis factor in thalassemia. Am J Hematol. 2002;70:100–6.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Suvachananonda T, Wankham A, Srihirun S, Tanratana P, Unchern S, Fucharoen S, et al. Decreased nitrite levels in erythrocytes of children with β-thalassemia/hemoglobin E. Nitric Oxide. 2013;33:1–5.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    El-Hady SB, Farahat MH, Atfy M, Elhady MA. Nitric oxide metabolites and arginase I levels in β-thalassemic patients: an Egyptian study. Ann Hematol. 2012;91:1193–200.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Rother RP, Bell L, Hillmen P, Glanwin M. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA. 2005;293:1653–62.

    CAS  Article  PubMed  Google Scholar 

  22. 22.

    Uaprasert N, Rojnuckarin P, Bhokaisawan N, Settapiboon R, Wacharaprechanont T, Amornsiriwat S, et al. Elevated serum transferrin receptor levels in common types of thalassemia heterozygotes in Southeast Asia: a correlation with genotypes and red cell indices. Clin Chim Acta. 2009;403:110–3.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging. 2015;16:233–70.

    Article  PubMed  Google Scholar 

  24. 24.

    Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health problem. Blood. 2010;115:4331–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Chueamuangphan N, Patumanond J, Wongtheptien W, Nawarawong W, Sukonthasarn A, Chuncharunee S, et al. Benefits of chronic blood transfusion in hemoglobin E/β thalassemia with pulmonary arterial hypertension. Int J Gen Med. 2014;7:411–6.

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Shalev H, Kapelushnik J, Moser A, Knobler H, Tamary H. Hypocholesterolemia in chronic anemias with increased erythropoietic activity. Am J Hematol. 2007;82:199–202.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Ricchi P, Ammirabile M, Spasiano A, Costantini S, Di Matola T, Cinque P, et al. Hypocholesterolemia in adult patients with thalassemia: a link with the severity of genotype in thalassemia intermedia patients. Eur J Haematol. 2009;82:219–22.

    Article  PubMed  Google Scholar 

  28. 28.

    Thijssen DH, Dawson EA, Black MA, Hopman MT, Cable NT, Green DJ. Heterogeneity in conduit artery function in humans: impact of arterial size. Am J Physiol Heart Circ Physiol. 2008;295:H1927–34.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Olson JS, Foley EW, Rogge C, Tsai AL, Doyle MP, Lemon DD. No scavenging and the hypertensive effect of hemoglobin-based blood substitutes. Free Radic Biol Med. 2004;36:685–97.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Schaer DJ, Buehler PW, Alayash AI, Belcher JD, Vercellotti GM. Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins. Blood. 2013;121:1276–84.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Detchaporn P, Kukongviriyapan U, Prawan A, Jetsrisuparb A, Greenwald SE, Kukongviriyapan V. Altered vascular function, arterial stiffness, and antioxidant gene responses in pediatric thalassemia patients. Pediatr Cardiol. 2012;33:1054–60.

    Article  PubMed  Google Scholar 

  32. 32.

    Park JY, Pillinger MH, Abramson SB. Prostaglandin E2 synthesis and secretion: the role of PGE2 synthases. Clin Immunol. 2006;119:229–40.

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Graido-Gonzalez E, Doherty JC, Bergreen EW, Organ G, Telfer M, McMillen MA. Plasma endothelin-1, cytokine, and prostaglandin E2 levels in sickle cell disease and acute vaso-occlusive sickle crisis. Blood. 1998;92:2551–5.

    CAS  PubMed  Google Scholar 

  34. 34.

    Viprakasit V, Kankirawatana S, Akarasereenont P, Durongpisitkul K, Chotewuttakorn S, Tanphaichitr VS. Baseline levels of plasma endothelin-1 (ET-1) and changes during transfusion in thalassemic patients. Am J Hematol. 2002;70:260–2.

    Article  PubMed  Google Scholar 

  35. 35.

    Dittman WA, Majerus PW. Structure and function of thrombomodulin: a natural anticoagulant. Blood. 1990;75:329–36.

    CAS  PubMed  Google Scholar 

  36. 36.

    Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood. 2007;109:3161–72.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Takano S, Kimura S, Ohdama S, Aoki N. Plasma thrombomodulin in health and diseases. Blood. 1990;76:2024–9.

    CAS  PubMed  Google Scholar 

  38. 38.

    Seigneur M, Dufourcq P, Conri C, Constans J, Mercie P, Pruvost A, et al. Levels of plasma thrombomodulin are increased in atheromatous arterial disease. Thromb Res. 1993;71:423–31.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Salomaa V, Matei C, Aleksic N, Sansores-Garcia L, Folsom AR, Juneja H, et al. Soluble thrombomodulin as a predictor of incident coronary heart disease and symptomless carotid artery atherosclerosis in the Atherosclerosis Risk in Communities (ARIC) Study: a case-cohort study. Lancet. 1999;353:1729–34.

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Kanavaki I, Makrythanasis P, Lazaropoulou C, Tsironi M, Kattamis A, Rombos I, et al. Soluble endothelial adhesion molecules and inflammation markers in patients with beta-thalassemia intermedia. Blood Cells Mol Dis. 2009;43:230–4.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Atichartakarn V, Chuncharunee S, Archararit N, Udomsubpayakul U, Aryurachai K. Intravascular hemolysis, vascular endothelial cell activation and thrombophilia in splenectomized patients with hemoglobin E/β-thalassemia disease. Acta Haematol. 2014;132:100–7.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

The study was granted by the Ratchadapiseksompotch Fund, Faculty of Medicine, Chulalongkorn University.

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Correspondence to Sudarat Satitthummanid.

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Satitthummanid, S., Uaprasert, N., Songmuang, S.B. et al. Depleted nitric oxide and prostaglandin E2 levels are correlated with endothelial dysfunction in β-thalassemia/HbE patients. Int J Hematol 106, 366–374 (2017). https://doi.org/10.1007/s12185-017-2247-8

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Keywords

  • β-Thalassemia/HbE
  • Endothelial dysfunction
  • Nitric oxide
  • Prostaglandin E2
  • Thrombomodulin