Abstract
Patients with thalassemia major are susceptible to cardiovascular complications by mechanisms not fully understood. Although overt cardiovascular complications usually occur after puberty, their underlying pathogenesis may begin much earlier. This study investigated whether there were early changes in vascular endothelial function and arterial stiffness in young patients with beta-thalassemia and hemoglobin E, and whether these changes were associated with oxidative stress and expression of antioxidant genes. The study recruited 30 pediatric patients and 30 age-matched control subjects. Compared with the control subjects, the patients had increased levels of oxidant biomarkers including malondialdehyde, protein carbonyl, and non–transferrin-bound iron and a decreased glutathione redox ratio. There were clear signs of vascular endothelial dysfunction and increased arterial stiffness, as shown by marked suppression of forearm blood flow after reactive hyperemia and increased pulse-wave velocity in the trunk and legs. The changes in FBF were associated with oxidative stress markers and free iron. An adaptive antioxidant gene response was activated in blood mononuclear cells, as shown by upregulation of GCLC and Bach-1 mRNA but downregulation of heme oxygenase-1 and thioredoxin mRNA. The results highlight the vascular changes seen even in young patients during treatment. These changes were associated with oxidative stress and suggest an adaptive response that serves to protect host cells from further oxidative damage.
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Aessopos A, Farmakis D, Hatziliami A, Fragodimitri C, Karabatsos F, Joussef J et al (2004) Cardiac status in well-treated patients with thalassemia major. Eur J Haematol 73:359–366
Aessopos A, Farmakis D, Tsironi M, Diamanti-Kandarakis E, Matzourani M, Fragodimiri C et al (2007) Endothelial function and arterial stiffness in sickle-thalassemia patients. Atherosclerosis 191:427–432
Aggeli C, Antoniades C, Cosma C, Chrysohoou C, Tousoulis D, Ladis V et al (2005) Endothelial dysfunction and inflammatory process in transfusion-dependent patients with beta-thalassemia major. Int J Cardiol 105:80–84
Aronson D (2003) Cross-linking of glycated collagen in the pathogenesis of arterial and myocardial stiffening of aging and diabetes. J Hypertens 21:3–12
Atkinson J (2008) Age-related medial elastocalcinosis in arteries: mechanisms, animal models, and physiological consequences. J Appl Physiol 105:1643–1651
Butthep P, Bunyaratvej A, Funahara Y, Kitaguchi H, Fucharoen S, Sato S et al (1995) Alterations in vascular endothelial cell-related plasma proteins in thalassaemic patients and their correlation with clinical symptoms. Thromb Haemost 74:1045–1049
Chakraborty D, Bhattacharyya M (2001) Antioxidant defense status of red blood cells of patients with beta-thalassemia and Ebeta-thalassemia. Clin Chim Acta 305:123–129
Cheung YF, Chan GC, Ha SY (2002) Arterial stiffness and endothelial function in patients with beta-thalassemia major. Circulation 106:2561–2566
Cunningham MJ, Macklin EA, Neufeld EJ, Cohen AR (2004) Complications of beta-thalassemia major in North America. Blood 104:34–39
Dhakshinamoorthy S, Jain AK, Bloom DA, Jaiswal AK (2005) Bach1 competes with Nrf2 leading to negative regulation of the antioxidant response element (ARE)-mediated NAD(P)H:quinone oxidoreductase 1 gene expression and induction in response to antioxidants. J Biol Chem 280:16891–16900
Domenica Cappellini M, Tavazzi D, Duca L, Marelli S, Fiorelli G (2000) Non–transferrin-bound iron, iron-related oxidative stress, and lipid peroxidation in beta-thalassemia intermedia. Transfus Sci 23:245–246
Farombi EO, Surh YJ (2006) Heme oxygenase-1 as a potential therapeutic target for hepatoprotection. J Biochem Mol Biol 39:479–491
Hahalis G, Alexopoulos D, Kremastinos DT, Zoumbos NC (2005) Heart failure in beta-thalassemia syndromes: a decade of progress. Am J Med 118:957–967
Jeyapaul J, Jaiswal AK (2000) Nrf2 and c-Jun regulation of antioxidant response element (ARE)-mediated expression and induction of gamma-glutamylcysteine synthetase heavy subunit gene. Biochem Pharmacol 59:1433–1439
Jison ML, Munson PJ, Barb JJ, Suffredini AF, Talwar S, Logun C et al (2004) Blood mononuclear cell gene expression profiles characterize the oxidant, hemolytic, and inflammatory stress of sickle cell disease. Blood 104:270–280
Jittangprasert P, Wilairat P, Pootrakul P (2004) Comparison of colorimetry and electrothermal atomic absorption spectroscopy for the quantification of non–transferrin-bound iron in human sera. Southeast Asian J Trop Med Public Health 35:1039–1044
Jones DP, Go YM, Anderson CL, Ziegler TR, Kinkade JM Jr, Kirlin WG (2004) Cysteine/cystine couple is a newly recognized node in the circuitry for biologic redox signaling and control. FASEB J 18:1246–1248
Kukongviriyapan V, Somparn N, Senggunprai L, Prawan A, Kukongviriyapan U, Jetsrisuparb A (2008) Endothelial dysfunction and oxidant status in pediatric patients with hemoglobin E-beta thalassemia. Pediatr Cardiol 29:130–135
Laurent S, Katsahian S, Fassot C, Tropeano AI, Gautier I, Laloux B et al (2003) Aortic stiffness is an independent predictor of fatal stroke in essential hypertension. Stroke 34:1203–1206
Loukogeorgakis S, Dawson R, Phillips N, Martyn CN, Greenwald SE (2002) Validation of a device to measure arterial pulse wave velocity by a photoplethysmographic method. Physiol Meas 23:581–596
Mattace-Raso FU, van der Cammen TJ, Hofman A, van Popele NM, Bos ML, Schalekamp MA et al (2006) Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam study. Circulation 113:657–663
Naka KK, Tweddel AC, Doshi SN, Goodfellow J, Henderson AH (2006) Flow-mediated changes in pulse-wave velocity: a new clinical measure of endothelial function. Eur Heart J 27:302–309
Nguyen T, Yang CS, Pickett CB (2004) The pathways and molecular mechanisms regulating Nrf2 activation in response to chemical stress. Free Radic Biol Med 37:433–441
Olivieri NF (1999) The beta-thalassemias. N Engl J Med 341:99–109
Ryter SW, Alam J, Choi AM (2006) Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev 86:583–650
Somparn N, Kukongviriyapan U, Tassaneeyakul W, Jetsrisuparb A, Kukongviriyapan V (2007) Modification of CYP2E1 and CYP3A4 activities in haemoglobin E-beta thalassemia patients. Eur J Clin Pharmacol 63:43–50
Surh YJ, Kundu JK, Li MH, Na HK, Cha YN (2009) Role of Nrf2-mediated heme oxygenase-1 upregulation in adaptive survival response to nitrosative stress. Arch Pharm Res 32:1163–1176
Weatherall DJ (2000) Introduction to the problem of hemoglobin E-beta thalassemia. J Pediatr Hematol Oncol 22:551
Acknowledgment
This work was supported by grant-in-aid from Khon Kaen University and a research fund from Faculty of Medicine, Khon Kaen University. The PWV equipment was provided by a British Council PMI2 Grant (#RC53) to Upa Kukongviriyapan and Stephen E. Greenwald.
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Detchaporn, P., Kukongviriyapan, U., Prawan, A. et al. Altered Vascular Function, Arterial Stiffness, and Antioxidant Gene Responses in Pediatric Thalassemia Patients. Pediatr Cardiol 33, 1054–1060 (2012). https://doi.org/10.1007/s00246-012-0225-8
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DOI: https://doi.org/10.1007/s00246-012-0225-8