Archives of Gynecology and Obstetrics

, Volume 298, Issue 2, pp 405–413 | Cite as

High-density lipoproteins (HDL) composition and function in preeclampsia

  • Yael Einbinder
  • Tal Biron-Shental
  • Moran Agassi-Zaitler
  • Keren Tzadikevitch-Geffen
  • Jacob Vaya
  • Soliman Khatib
  • Meital Ohana
  • Sydney Benchetrit
  • Tali Zitman-GalEmail author
Gynecologic Endocrinology and Reproductive Medicine



To evaluate (a) the properties of high-density lipoproteins (HDL)/cholesterol, which include apolipoprotein A-1 (ApoA1) and paraoxonase1 (PON1), both are negative predictors of cardiovascular risk and (b) HDL function, among women with preeclampsia (PE). PE is a multi-system disorder, characterized by onset of hypertension and proteinuria or other end-organ dysfunction in the second half of pregnancy. Preeclampsia is associated with increased risk for later cardiovascular disease. The inverse association between HDL, cholesterol levels and the risk of developing atherosclerotic cardiovascular disease is well-established.


Twenty-five pregnant women [19 with PE and 6 with normal pregnancy (NP)] were recruited during admission for delivery. HDL was isolated from blood samples. PON1 activity and HDL were analyzed. An in vitro model of endothelial cells was used to evaluate the effect of HDL on the transcription response of vascular cell adhesion molecule-1 (VCAM-1) and endothelial nitric oxide synthase (eNOS) mRNA expression.


PON1 activity (units/ml serum) was lower in the PE group compared to normal pregnancy (NP) (6.51 ± 0.73 vs. 9.98 ± 0.54; P = 0.015). Increased ApoA1 was released from PE-HDL as compared to NP-HDL (3.54 ± 0.72 vs. 0.89 ± 0.35; P = 0.01). PE-HDL exhibited increased VCAM-1 mRNA expression and decreased eNOS mRNA expression on TNF-α stimulated endothelial cells as compared to NP-HDL.


HDL from women with PE reduced PON1 activity and increased ApoA1 release from HDL particles. This process was associated with increased HDL diameter, suggesting impaired HDL anti-oxidant activity. These changes might contribute to higher long-term cardiovascular risks among women with PE.


Preeclampsia HDL ApoA1 PON1 eNOS VCAM-1 



This study is part of the basic science requirements of M. Agassi-Zaitler, Department of Obstetrics and Gynecology, Meir Medical Center, Kfar Saba, Israel. We thank the delivery room staff of Meir Medical Center for helping recruit women to the study. We thank Prof. M. Aviram and N. Volkova from the Lipid Research Laboratory Technion, Rappaport Faculty of Medicine, Rambam Medical Center, Haifa, Israel for teaching us the HDL isolation method. We thank D. Atrahimovich from the Laboratory of Oxidative Stress and Human Diseases in the Migdal-Galilee Technology Center, Israel for helping with the PON1 activity assay. We thank F. Schreiber, MSc for editing the manuscript and N. Jelin, MA for assistance with the statistical analysis. They are both employees of Meir Medical Center.

Author contributions

YE, TBS, JV, SB and TZG conception and design of research; YE, KTG, MAZ and TZG data and blood collection; MO, KTG, MAZ, SK and TZG performed experiments; TZG, MO and SK analyzed data, interpreted results and prepared figures; YE, TBS, JV, SB and TZG drafted manuscript; YE, SB and TZG edited and revised manuscript; all authors approved the final version of manuscript.


This work was supported by the Mintz-Law Foundation (Y. Einbinder) from the Sackler Faculty of Medicine, Tel Aviv University, Israel.

Compliance with ethical standards

Conflict of interest

All authors have no conflicts of interest.


  1. 1.
    Noris M, Perico N, Remuzzi G (2005) Mechanisms of disease: pre-eclampsia. Nat Clin Pract Nephrol 1:98–114CrossRefPubMedGoogle Scholar
  2. 2.
    Sibai B, Dekker G, Kupferminc M (2005) Pre-eclampsia. Lancet 365:785–799CrossRefPubMedGoogle Scholar
  3. 3.
    Myatt L, Webster RP (2009) Vascular biology of preeclampsia. J Thromb Haemost 7:375–384CrossRefPubMedGoogle Scholar
  4. 4.
    Scantlebury DC, Hayes SN (2014) How does preeclampsia predispose to future cardiovascular disease? Curr Hypertens Rep 16:472CrossRefPubMedGoogle Scholar
  5. 5.
    Kopecky C, Genser B, Drechsler C et al (2015) Quantification of HDL proteins, cardiac events, and mortality in patients with type 2 diabetes on hemodialysis. Clin J Am Soc Nephrol 10:224–231CrossRefPubMedGoogle Scholar
  6. 6.
    Roberts JM (1998) Endothelial dysfunction in preeclampsia. Semin Reprod Endocrinol 16:5–15CrossRefPubMedGoogle Scholar
  7. 7.
    Flavahan NA (1992) Atherosclerosis or lipoprotein-induced endothelial dysfunction. Potential mechanisms underlying reduction in EDRF/nitric oxide activity. Circulation 85:1927–1938CrossRefPubMedGoogle Scholar
  8. 8.
    Ray K, Wainwright NW, Visser L et al (2012) Changes in HDL cholesterol and cardiovascular outcomes after lipid modification therapy. Heart 98:780–785CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Toth PP, Barter PJ, Rosenson RS et al (2013) High-density lipoproteins: a consensus statement from the National Lipid Association. J Clin Lipidol 7:484–525CrossRefPubMedGoogle Scholar
  10. 10.
    Gansevoort RT, Correa-Rotter R, Hemmelgarn BR et al (2013) Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet 382:339–352CrossRefPubMedGoogle Scholar
  11. 11.
    Maynard SE, Min JY, Merchan J et al (2003) Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest 111:649–658CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Barker DJ (2004) The developmental origins of well-being. Philos Trans R Soc Lond B Biol Sci 359:1359–1366CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Rich-Edwards JW, Fraser A, Lawlor DA, Catov JM (2014) Pregnancy characteristics and women’s future cardiovascular health: an underused opportunity to improve women’s health? Epidemiol Rev 36:57–70CrossRefPubMedGoogle Scholar
  14. 14.
    Belo L, Caslake M, Gaffney D et al (2002) Changes in LDL size and HDL concentration in normal and preeclamptic pregnancies. Atherosclerosis 162:425–432CrossRefPubMedGoogle Scholar
  15. 15.
    Gbandjaba NY, Ghalim N, Hassar M et al (2012) Paraoxonase activity in healthy, diabetic, and hemodialysis patients. Clin Biochem 45:470–474CrossRefPubMedGoogle Scholar
  16. 16.
    Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM (2004) Antiinflammatory properties of HDL. Circ Res 95:764–772CrossRefPubMedGoogle Scholar
  17. 17.
    Phillips JC, Wriggers W, Li Z, Jonas A, Schulten K (1997) Predicting the structure of apolipoprotein A-I in reconstituted high-density lipoprotein disks. Biophys J 73:2337–2346CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Demir B, Demir S, Atamer Y et al (2011) Serum levels of lipids, lipoproteins and paraoxonase activity in pre-eclampsia. J Int Med Res 39:1427–1431CrossRefPubMedGoogle Scholar
  19. 19.
    Riwanto M, Landmesser U (2013) High density lipoproteins and endothelial functions: mechanistic insights and alterations in cardiovascular disease. J Lipid Res 54:3227–3243CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Shroff R, Speer T, Colin S et al (2014) HDL in children with CKD promotes endothelial dysfunction and an abnormal vascular phenotype. J Am Soc Nephrol 25:2658–2668CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Mackness MI, Durrington PN (1995) HDL, its enzymes and its potential to influence lipid peroxidation. Atherosclerosis 115:243–253CrossRefPubMedGoogle Scholar
  22. 22.
    Demirci O, Tugrul AS, Dolgun N, Sozen H, Eren S (2011) Serum lipids level assessed in early pregnancy and risk of pre-eclampsia. J Obstet Gynaecol Res 37:1427–1432CrossRefPubMedGoogle Scholar
  23. 23.
    Aviram M (1983) Plasma lipoprotein separation by discontinuous density gradient ultracentrifugation in hyperlipoproteinemic patients. Biochem Med 30:111–118CrossRefPubMedGoogle Scholar
  24. 24.
    Khersonsky O, Tawfik DS (2006) Chromogenic and fluorogenic assays for the lactonase activity of serum paraoxonases. Chem BioChem 7:49–53Google Scholar
  25. 25.
    Rashid G, Benchetrit S, Fishman D, Bernheim J (2004) Effect of advanced glycation end-products on gene expression and synthesis of TNF-alpha and endothelial nitric oxide synthase by endothelial cells. Kidney Int 66:1099–1106CrossRefPubMedGoogle Scholar
  26. 26.
    Gugliucci A, Caccavello R, Kotani K, Sakane N, Kimura S (2013) Enzymatic assessment of paraoxonase 1 activity on HDL subclasses: a practical zymogram method to assess HDL function. Clin Chim Acta 415:162–168CrossRefPubMedGoogle Scholar
  27. 27.
    Cohen E, Aviram M, Khatib S, Volkova N, Vaya J (2016) Human carotid atherosclerotic plaque protein(s) change HDL protein(s) composition and impair HDL anti-oxidant activity. BioFactors 42:115–128PubMedGoogle Scholar
  28. 28.
    Zitman-Gal T, Golan E, Green J, Bernheim J, Benchetrit S (2012) Vitamin D receptor activation in a diabetic-like environment: potential role in the activity of the endothelial pro-inflammatory and thioredoxin pathways. J Steroid Biochem Mol Biol 132:1–7CrossRefPubMedGoogle Scholar
  29. 29.
    Einbinder Y, Ohana M, Benchetrit S et al (2016) Glucagon-like peptide-1 and vitamin D: anti-inflammatory response in diabetic kidney disease in db/db mice and in cultured endothelial cells. Diabetes Metab Res Rev 32:805–815CrossRefPubMedGoogle Scholar
  30. 30.
    Luscher TF, Landmesser U, von Eckardstein A, Fogelman AM (2014) High-density lipoprotein: vascular protective effects, dysfunction, and potential as therapeutic target. Circ Res 114:171–182CrossRefPubMedGoogle Scholar
  31. 31.
    Feig JE, Hewing B, Smith JD, Hazen SL, Fisher EA (2014) High-density lipoprotein and atherosclerosis regression: evidence from preclinical and clinical studies. Circ Res 114:205–213CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Hedrick CC, Castellani LW, Wong H, Lusis AJ (2001) In vivo interactions of apoA-II, apoA-I, and hepatic lipase contributing to HDL structure and antiatherogenic functions. J Lipid Res 42:563–570PubMedGoogle Scholar
  33. 33.
    van der Steeg WA, Holme I, Boekholdt SM et al (2008) High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: the IDEAL and EPIC-Norfolk studies. J Am Coll Cardiol 51:634–642CrossRefPubMedGoogle Scholar
  34. 34.
    Regieli JJ, Jukema JW, Doevendans PA et al (2009) Paraoxonase variants relate to 10-year risk in coronary artery disease: impact of a high-density lipoprotein-bound antioxidant in secondary prevention. J Am Coll Cardiol 54:1238–1245CrossRefPubMedGoogle Scholar
  35. 35.
    Bhattacharyya T, Nicholls SJ, Topol EJ et al (2008) Relationship of paraoxonase 1 (PON1) gene polymorphisms and functional activity with systemic oxidative stress and cardiovascular risk. JAMA 299:1265–1276CrossRefPubMedGoogle Scholar
  36. 36.
    Shih DM, Gu L, Xia YR et al (1998) Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Nature 394:284–287CrossRefPubMedGoogle Scholar
  37. 37.
    Genc H, Uzun H, Benian A et al (2011) Evaluation of oxidative stress markers in first trimester for assessment of preeclampsia risk. Arch Gynecol Obstet 284:1367–1373CrossRefPubMedGoogle Scholar
  38. 38.
    Uzun H, Benian A, Madazli R, Topcuoglu MA, Aydin S, Albayrak M (2005) Circulating oxidized low-density lipoprotein and paraoxonase activity in preeclampsia. Gynecol Obstet Invest 60:195–200CrossRefPubMedGoogle Scholar
  39. 39.
    Hubel CA, McLaughlin MK, Evans RW, Hauth BA, Sims CJ, Roberts JM (1996) Fasting serum triglycerides, free fatty acids, and malondialdehyde are increased in preeclampsia, are positively correlated, and decrease within 48 hours post partum. Am J Obstet Gynecol 174:975–982CrossRefPubMedGoogle Scholar
  40. 40.
    Rosing U, Samsioe G, Olund A, Johansson B, Kallner A (1989) Serum levels of apolipoprotein A-I, A-II and HDL-cholesterol in second half of normal pregnancy and in pregnancy complicated by pre-eclampsia. Horm Metab Res 21:376–382CrossRefPubMedGoogle Scholar
  41. 41.
    Ramet ME, Ramet M, Lu Q et al (2003) High-density lipoprotein increases the abundance of eNOS protein in human vascular endothelial cells by increasing its half-life. J Am Coll Cardiol 41:2288–2297CrossRefPubMedGoogle Scholar
  42. 42.
    Tai SC, Robb GB, Marsden PA (2004) Endothelial nitric oxide synthase: a new paradigm for gene regulation in the injured blood vessel. Arterioscler Thromb Vasc Biol 24:405–412CrossRefPubMedGoogle Scholar
  43. 43.
    Mineo C, Shaul PW (2012) Novel biological functions of high-density lipoprotein cholesterol. Circ Res 111:1079–1090CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Kaseda R, Jabs K, Hunley TE et al (2015) Dysfunctional high-density lipoproteins in children with chronic kidney disease. Metabolism 64:263–273CrossRefPubMedGoogle Scholar
  45. 45.
    Ortiz-Munoz G, Couret D, Lapergue B et al (2016) Dysfunctional HDL in acute stroke. Atherosclerosis 253:75–80CrossRefPubMedGoogle Scholar
  46. 46.
    Szarka A, Rigo J Jr, Lazar L, Beko G, Molvarec A (2010) Circulating cytokines, chemokines and adhesion molecules in normal pregnancy and preeclampsia determined by multiplex suspension array. BMC Immunol 11:59CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Fainaru O, Lichtenberg D, Pinchuk I, Almog B, Gamzu R, Kupferminc M (2003) Preeclampsia is associated with increased susceptibility of serum lipids to copper-induced peroxidation in vitro. Acta Obstet Gynecol Scand 82:711–715CrossRefPubMedGoogle Scholar
  48. 48.
    Wakatsuki A, Ikenoue N, Okatani Y, Shinohara K, Fukaya T (2000) Lipoprotein particles in preeclampsia: susceptibility to oxidative modification. Obstet Gynecol 96:55–59PubMedGoogle Scholar
  49. 49.
    Sarandol E, Safak O, Dirican M, Uncu G (2004) Oxidizability of apolipoprotein B-containing lipoproteins and serum paraoxonase/arylesterase activities in preeclampsia. Clin Biochem 37:990–996CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Yael Einbinder
    • 1
    • 2
  • Tal Biron-Shental
    • 2
    • 3
  • Moran Agassi-Zaitler
    • 3
  • Keren Tzadikevitch-Geffen
    • 2
    • 3
  • Jacob Vaya
    • 4
  • Soliman Khatib
    • 4
  • Meital Ohana
    • 1
  • Sydney Benchetrit
    • 1
    • 2
  • Tali Zitman-Gal
    • 1
    • 2
    Email author
  1. 1.Department of Nephrology and HypertensionMeir Medical CenterKfar SabaIsrael
  2. 2.Sackler Faculty of MedicineTel Aviv UniversityTel AvivIsrael
  3. 3.Department of Obstetrics and GynecologyMeir Medical CenterKfar SabaIsrael
  4. 4.Laboratory of Oxidative Stress and Human DiseasesMigdal-Galilee Technology Center, Tel Hai CollegeKiryat ShmonaIsrael

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