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Lipid peroxidation as risk factor for endothelial dysfunction in antiphospholipid syndrome patients

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Abstract

The aim of this study was to evaluate oxidative stress markers and it relations to endothelial damage as risk factor for thrombosis in patients with primary (PAPS) and secondary (SAPS) antiphospholipid syndrome (APS) in correlation to traditional risk factors. Flow-mediated (FMD) and nitroglycerine (NMD)-induced dilation of the brachial artery were studied in 140 APS patients (90 PAPS, 50 SAPS) and 40 controls matched by age, sex, and conventional risk factors for atherosclerosis. Markers of oxidative stress, lipid hydroperoxydes (LOOH), advanced oxidation protein products (AOPP), total sulfhydryl groups (tSHG), and paraoxonase 1 activity (PON1) were determined by spectrophotometric method. Oxidative stress dominates in APS patients. LOOH and AOPP correlate to lipid fractions (p < 0.05), unlike PON1, tSHG that correlated to antiphospholipid antibody positivity (p < 0.05). FMD was lower in APS patients comparing to controls (p < 0.001). Cholesterol is independent variable for FMD impairment in control group (p = 0.011); LOOH in PAPS (p = 0.004); LOOH, aCL, and triglycerides in SAPS patients (p = 0.009, p = 0.049, and p = 0.012, respectively). Combined predictive of aCL and LOOH is better for FMD impairment than LOOH alone in both PAPS and SAPS patients (AUC 0.727, p = 0.001, 95 % CI 0.616–0.837 and AUC 0.824, p˂0.001, 95 % CI 0.690–0.957, respectively). Lipid peroxidation is independent predictor for endothelial dysfunction in APS patients. We demonstrated synergistic effect of aCL and LOOH as risk for endothelial impairment in both PAPS and SAPS patients.

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References

  1. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. (2006) International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4:295–306

    Article  CAS  PubMed  Google Scholar 

  2. Foltyn Zadura A, Memon AA, Stojanovich L, Perricone C, Conti F, Valesini G, et al. (2015) Factor H autoantibodies in patients with antiphospholipid syndrome and thrombosis. J Rheumatol 42(10):1786–1793

    Article  PubMed  Google Scholar 

  3. Becarevic M, Stojanovich L, Ignjatovic S, Dopsaj V (2016) The IgM isotype of anti-annexin A5 antibodies and multiple positivity of conventional antiphospholipid antibodies: increasing the number of clinical manifestations of primary antiphospholipid syndrome. Clin Rheumatol. doi:10.1007/s10067-016-3230-0

    Google Scholar 

  4. Shoenfeld Y, Blank M, Cervera R, Font J, Raschi E, Meroni P (2006) Infectious origin of the antiphospholipid syndrome. Ann Rheum Dis 65:2–6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wilson WA, Gharavi AE, Koike T, Lockshin MD, Branch DW, Piette JC, et al. (1999) International consensus statement on preliminary classification criteria for definitive antiphospholipid syndrome. Arthritis Rheum 42:1309–1311

    Article  CAS  PubMed  Google Scholar 

  6. Mercanoglu F, Erdogan D, Oflaz H, Kucukkaya R, Selcukbiricik F, Gu L, Inanc M (2004) Impaired brachial endothelial function in patients with primary anti-phospholipid syndrome. Int J Clin Pract 58:1003–1007

    Article  CAS  PubMed  Google Scholar 

  7. Der H, Kerekes G, Veres K, Szodoray P, Toth J, Lakos G, et al. (2007) Impaired endothelial function and increased carotid intima-media thickness in association with elevated von Willebrand antigen level in primary antiphospholipid syndrome. Lupus 16:497–503

    Article  CAS  PubMed  Google Scholar 

  8. Kiss E, Soltesz P, Der H, Kocsis Z, Tarr T, Bhattoa H, et al. (2006) Reduced flow-mediated vasodilation as a marker for cardiovascular complications in lupus patients. J Autoimmun 27(4):211–217

    Article  CAS  PubMed  Google Scholar 

  9. Stalc M, Poredos P, Peternel P, Tomsic M, Sebestjen M, Kveder T (2006) Endothelial function is impaired in patients with primary antiphospholipid syndrome. Thromb Res 118:455–461

    Article  CAS  PubMed  Google Scholar 

  10. Ames PR, Batuca JR, Ciampa A, Iannaccone L, Delgado Alves J (2010) Clinical relevance of nitric oxide metabolites and nitrative stress in thrombotic primary antiphospholipid syndrome. J Rheumatol 37:2523–2530

    Article  CAS  PubMed  Google Scholar 

  11. Bilora F, Sartori M (2008) Flow-mediated arterial dilation in primary antiphospholipid syndrome. Angiology 59:717–720

    Article  PubMed  Google Scholar 

  12. Marai I, Shechter M, Langevitz P, Gilburd B, Rubenstein A, Matssura E, Sherer Y, Shoenfeld Y (2008) Anticardiolipin antibodies and endothelial function in patients with coronary arthery disease. Am J Cardiol 101:1094–1097

    Article  CAS  PubMed  Google Scholar 

  13. Soltész P, Kerekes G, Dér H, Szücs G, Szántó S, Kiss E, et al. (2011) Comparative assessment of vascular function in autoimmune rheumatic diseases: consideration of prevention and treatment. Autoimmun Rev 10:416–425

    Article  PubMed  Google Scholar 

  14. Zardi EM, Afeltra A (2010) Endothelial dysfunction and vascular stiffness in systemic lupus erythematosus: are they early markers of subclinical atherosclerosis? Autoimmun Rev 9:684–686

    Article  CAS  PubMed  Google Scholar 

  15. Mansour RB, Lassoued S, Gargouri B, El Gaïd A, Attia H, Fakhfakh F (2008) Increased levels of autoantibodies against catalase and superoxide dismutase associated with oxidative stress in patients with rheumatoid arthritis and systemic lupus erythematosus. Scand J Rheumatol 37:103–108

    Article  PubMed  Google Scholar 

  16. Alves D, Ames PR, Donohue S, Stanyer L, Nourooz-Zadeh J, Ravirajan C, Isenberg DA (2002) Antibodies to high-density lipoprotein and beta2-glycoproteinI are inversely correlated with paraoxonase activity in systemic lupus erythematosus and primary antiphospholipid syndrome. Arth Rheum 10:2686–2694

    Article  Google Scholar 

  17. Martinuzzo ME, Forastiero RR, Kordich L, Carreras LO (2001) Increased lipid peroxidation correlates with platelet activation but not with markers of endothelial cell and blood coagulation activation in patients with antiphospholipid antibodies. Br J Haematol 114:845–851

    Article  CAS  PubMed  Google Scholar 

  18. Tan EM, Cohen AS, Fries JF, Masi AT, McShane DJ, Rothfield NF, et al. (1982) The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25:1271–1277

    Article  CAS  PubMed  Google Scholar 

  19. Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH (1992) Derivation of the SLEDAI. A disease activity index for lupus patients.The committee on prognosis studies in SLE. Arthritis Rheum 35:630–640

    Article  CAS  PubMed  Google Scholar 

  20. Pengo V, Tripodi A, Reber G, et al. (2009) Subcommittee on lupus anticoagulant/antiphospholipid antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost 7(10):1737–1740

    Article  CAS  PubMed  Google Scholar 

  21. Pengo V, Biasiolo A, Pegoraro C, Cucchini U, Noventa F, Iliceto S (2005) Antibody profiles for the diagnosis of antiphospholipid syndrome. Thromb Haemost 93:1147–1152

    CAS  PubMed  Google Scholar 

  22. Gay C, Collins J, Gebicki JM (1999) Hydroperoxide assay with the ferric-xylenol orange complex. Anal Biochem 273:149–155

    Article  CAS  PubMed  Google Scholar 

  23. Witko-Sarsat V, Friedlander M, Nguyen Khoa T, Capeillere-Blandin C, Nguyen AT, Canteloup S, et al. (1998) Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure. J Immunol 161:2524–2532

    CAS  PubMed  Google Scholar 

  24. Ellman E (1959) Tissue sulfhydryl groups. Arch Biochem Biophys 82:70–77

    Article  CAS  PubMed  Google Scholar 

  25. Furlong C, Richter RJ, Seidel SL, Costa LG, Motulsky AG (1989) Spectrophotometric assays for the enzymatic hydrolysis of the active metabolites of chlorpyrifos and parathion by plasma paraoxonase/arylesterase. Anal Biochem 180:242–247

    Article  CAS  PubMed  Google Scholar 

  26. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, et al. (2002) 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 39:257–265

    Article  PubMed  Google Scholar 

  27. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, et al. (1992) Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet 340:1111–1115

    Article  CAS  PubMed  Google Scholar 

  28. Stojanovich L, Markovic O, Marisavljevic D, Elezovic I, Ilijevski N, Stanisavljevic N (2012) Influence of antiphospholipid antibody levels and type on thrombotic manifestations: results from the Serbian national cohort study. Lupus 21:338–345

    Article  CAS  PubMed  Google Scholar 

  29. Galli M, Luciani D, Bertolini G, Barbui T (2003) Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 1:1827–1832

    Article  Google Scholar 

  30. Stojanovich L, Djokovic A, Kontic M (2015) Antiphospholipid-mediated thrombosis: interplay between type of antibodies and localisation of lung, and cardiovascular incidences in primary antiphospholipid syndrome. Clin Exp Rheumatol 33:531–536

    PubMed  Google Scholar 

  31. Neville C, Rauch J, Kassis J, Chang ER, Joseph L, Le Comte M, Fortin PR (2003) Thromboembolic risk in patients with high levels anticardiolipin and multiple antiphospholipid antibodies. Thromb Haemost 90:108–115

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Nuttall SL, Heaton S, Piper MK, Martin U, Gordon C (2003) Cardiovascular risk in systemic lupus erythematosus—evidence of increased oxidative stress and dyslipidaemia. Rheumatology (Oxford) 42:758–762

    Article  CAS  Google Scholar 

  33. Kurien BT, Scofield RH (2003) Free radical mediated peroxidative damage in systemic lupus erythematosus. Life Sci 73:1655–1666

    Article  CAS  PubMed  Google Scholar 

  34. Frostegård J, Svenungsson E, Wu R, Gunnarsson I, Lundberg IE, Klareskog L, Hörkkö S, Witztum JL (2005) Lipid peroxidation is enhanced in patients with systemic lupus erythematosus and is associated with arterial and renal disease manifestation. Arthritis Rheum 52:192–200

    Article  PubMed  Google Scholar 

  35. Abou-Raya A, Hallous D, Fayed H (2004) 8-Isoprostaglandin F2 alpha: a potential index of lipid peroxidation in systemic lupus erythematosus. Clin Invest Med 27:306–311

    CAS  PubMed  Google Scholar 

  36. Horkko S, Miller E, Dudl E, Reaven P, Curtiss L, Zvaifler J, et al. (1996) Antiphospholipid antibodies are directed against epitopes of oxidized phospholipids. Recognition of cardiolipin by monoclonal antibodies to epitopes of oxidized low density lipoprotein J Clin Invest 98:815–825

    CAS  PubMed  Google Scholar 

  37. Sc B, Kim SJ, Sung MK (2002) Impaired antioxidant status and decreased dietary of antioxidants in patients with systemic lupus erythematosus. Rheumatol Int 22:238–243

    Article  Google Scholar 

  38. Taysi S, Gul M, Sari RA, Akcay F, Bakan N (2002) Serum oxidant/antioxidant status of patients with systemic lupus erythematosus. Clin Chem Lab Med 40:684–688

    CAS  PubMed  Google Scholar 

  39. Zhang L, Jin B, Li L, Block ER, Patel JM (2005) Nitric oxide-induced persistent inhibition and nitrosylation of active site cysteine residues of mitochondrial cytochrome-c oxidase in lung endothelial cells. Am J Physiol Cell Physiol 288:C840–C849

    Article  CAS  PubMed  Google Scholar 

  40. Morgan PE, Sturgess AD, Davies MJ (2005) Increased levels of serum protein oxidation and correlation with disease activity in systemic lupus erythematosus. Arthr Rheum 52:2069–2079

    Article  CAS  Google Scholar 

  41. Lambert M, Boullier A, Hachulla E, Fruchart JC, Teissier E, Hatron PY, et al. (2000) Paraoxonase activity is dramatically decreased in patients positive for anticardiolipin antibodies. Lupus 9:299–300

    Article  CAS  PubMed  Google Scholar 

  42. Ames PR, Nourooz-Zadeh J, Tommasino C, Alves J, Brancaccio V, Anggard EE (1998) Oxidative stress in primary antiphospholipid syndrome. Thromb Haemost 79:447–449

    CAS  PubMed  Google Scholar 

  43. Reis SE, Holubkov R, Smith AJC, Kelsey SF, Sharaf BL, Reichek N, et al. (2001) Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study. Am Heart J V 5:735–741

    Article  Google Scholar 

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Acknowledgments

We would like to thank all patients who participated in this study and our colleagues from numerous clinics in Serbia.

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Authors and Affiliations

  1. University Clinical Center “Bezanijska kosa”, Bezanijska kosa bb, Belgrade, 11070, Serbia

    Natasa Stanisavljevic, L. Stojanovich, D. Marisavljevic, A. Djokovic, L. Memon, S. Radovanovic, B. Todic & D. Lisulov

  2. Faculty of Medicine, University of Belgrade, Belgrade, Serbia

    D. Marisavljevic & A. Djokovic

  3. Clinical Center of Serbia, Faculty of Pharmacy Belgrade, University of Belgrade, Belgrade, Serbia

    V. Dopsaj

  4. Institute of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia

    J. Kotur-Stevuljevic

  5. Rakovica Community Health Center, Belgrade, Serbia

    J. Martinovic

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  1. Natasa Stanisavljevic
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Correspondence to Natasa Stanisavljevic.

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All procedures conducted in patients were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

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Funding

This work was supported by research grant number 175,041, and TR 32040 for 2011–2016, issued by the Ministry of Science of the Republic of Serbia. The funding source had no involvement in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit this article for publication.

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Stanisavljevic, N., Stojanovich, L., Marisavljevic, D. et al. Lipid peroxidation as risk factor for endothelial dysfunction in antiphospholipid syndrome patients. Clin Rheumatol 35, 2485–2493 (2016). https://doi.org/10.1007/s10067-016-3369-8

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