Skip to main content
SpringerLink
Log in

Preeclampsia and HELLP Syndrome: Impaired Mitochondrial Function in Umbilical Endothelial Cells

  • Original Article
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Preeclampsia (PE) and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome have been linked to congenital fetal disorders of mitochondrial fatty acid oxidation (FAO). Different incidences may argue for the association of noncongenital alterations of mitochondrial energy metabolism with PE/HELLP syndrome. We studied human umbilical vein endothelial cells [HUVEC] as selected part of the feto-placental unit from uncomplicated (n = 46) and diseased (n = 27; 17 PE and 10 HELLP) pregnancies by measuring the overall FAO, carnitine palmitoyltransferase 2 (CPT2), respiratory chain (RC) complexes I-V, citratesynthase (CS), lactatedehydrogenase (LDH), hexokinase (HK), phosphofructokinase (PFK), and energy rich phosphates. Maternal and infantile acylcarnitines in blood were investigated post partum. Overall FAO, RC complexes II-V, and CS were significantly compromised in HUVEC from complicated pregnancies; impairment of complexes I + III was not significant. CPT2 and energy charges were unaffected. Lactatedehydrogenase and PFK from complicated pregnancies were upregulated, and HK remained constant. In blood, carnitine was elevated in diseased women and their children, acylcarnitines were higher in affected infants. Impaired mitochondrial function in HUVEC is associated with PE/HELLP syndrome and may be involved in the pathophysiology of these diseases.

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

Similar content being viewed by others

References

  1. Baxter JK, Weinstein L. HELLP syndrome: the state of the art. Obstet Gynecol Surv. 2004;59(12):838–845.

    Article  PubMed  Google Scholar 

  2. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet. 2005;365(9461):785–799.

    Article  PubMed  Google Scholar 

  3. Brown MA, Hague WM, Higgins J, et al., and the Austalasian Society for the Study of Hypertension in Pregnancy. The detection, investigation and management of hypertension in pregnancy: full consensus statement. Aust N Z J Obstet Gynaecol. 2000;40(2):139–155.

    Article  CAS  PubMed  Google Scholar 

  4. Ibdah JA, Bennett MJ, Rinaldo P, et al. A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women. N Engl J Med. 1999;340(22):1723–1731.

    Article  CAS  PubMed  Google Scholar 

  5. Strauss AW, Bennett MJ, Rinaldo P, et al. Inherited long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and a fetal-maternal interaction cause maternal liver disease and other pregnancy complications. Semin Perinatol. 1999;23(2): 100–112.

    Article  CAS  PubMed  Google Scholar 

  6. Schoeman MN, Batey RG, Wilcken B. Recurrent acute fatty liver of pregnancy associated with a fatty-acid oxidation defect in the offspring. Gastroenterology. 1991;100(2):544–548.

    Article  CAS  PubMed  Google Scholar 

  7. Mutze S, Ahillen I, Rudnik-Schoeneborn S, et al. Neither maternal nor fetal mutation (E474Q) in the alpha-subunit of the trifunctional protein is frequent in pregnancies complicated by HELLP syndrome. J Perinat Med. 2007;35(1):76–78.

    Article  PubMed  CAS  Google Scholar 

  8. Wang R, Yang Z, Zhu JM, et al. Screening for G1528C mutation in mitochondrial trifunctional protein gene in pregnant women with severe preeclampsia and new born infant [in Chinese]. Zhonghua Fu Chan Ke Za Zhi. 2006; 41(10):672–675.

    PubMed  Google Scholar 

  9. Yang Z, Yamada J, Zhao Y, Strauss AW, Ibdah JA. Prospective screening for pediatric mitochondrial trifunctional protein defects in pregnancies complicated by liver disease. JAMA. 2002;288(17):2163–2166.

    Article  PubMed  Google Scholar 

  10. den Boer ME, Ijlst L, Wijburg FA, et al. Heterozygosity for the common LCHAD mutation (1528g>C) is not a major cause of HELLP syndrome and the prevalence of the mutation in the Dutch population is low. Pediatr Res. 2000;48(2): 151–154.

    Article  Google Scholar 

  11. Holub M, Bodamer OA, Item C, Muhl A, Pollak A, Stockler-Ipsiroglu S. Lack of correlation between fatty acid oxidation disorders and haemolysis, elevated liver enzymes, low platelets (HELLP) syndrome? Acta Paediatr. 2005;94(1):48–52.

    Article  CAS  PubMed  Google Scholar 

  12. Illsley NP. Glucose transporters in the human placenta. Placenta. 2000;21(1):14–22.

    Article  CAS  PubMed  Google Scholar 

  13. Faivre L, Cormier-Daire V, Chretien D, et al. Determination of enzyme activities for prenatal diagnosis of respiratory chain deficiency. Prenat Diagn. 2000;20(9):732–737.

    Article  CAS  PubMed  Google Scholar 

  14. Shekhawat P, Bennett MJ, Sadovsky Y, Nelson DM, Rakheja D, Strauss AW. Human placenta metabolizes fatty acids: implications for fetal fatty acid oxidation disorders and maternal liver diseases. Am J Physiol Endocrinol Metab. 2003; 284(6):E1098–E1105.

    Article  CAS  PubMed  Google Scholar 

  15. Rakheja D, Bennett MJ, Foster BM, Domiati-Saad R, Rogers BB. Evidence for fatty acid oxidation in human placenta, and the relationship of fatty acid oxidation enzyme activities with gestational age. Placenta. 2002;23(5):447–450.

    Article  CAS  PubMed  Google Scholar 

  16. Oey NA, Ruiter JP, Attie-Bitach T, Ijlst L, Wanders RJ, Wijburg FA. Fatty acid oxidation in the human fetus: implications for fetal and adult disease. J Inherit Metab Dis. 2006;29(1): 71–75.

    Article  CAS  PubMed  Google Scholar 

  17. Knopp RH, Warth MR, Charles D, et al. Lipoprotein metabolism in pregnancy, fat transport to the fetus, and the effects of diabetes. Biol Neonate. 1986;50(6):297–317.

    Article  CAS  PubMed  Google Scholar 

  18. Thiele IG, Niezen-Koning KE, van Gennip AH, Aarnoudse JG. Increased plasma carnitine concentrations in preeclampsia. Obstet Gynecol. 2004;103(5 pt 1):876–880.

    Article  CAS  PubMed  Google Scholar 

  19. Torbergsen T, Oian P, Mathiesen E, Borud O. Pre-eclampsia—a mitochondrial disease? Acta Obstet Gynecol Scand. 1989; 68(2):145–148.

    Article  CAS  PubMed  Google Scholar 

  20. He L, Wang Z, Sun Y. Reduced amount of cytochrome c oxidase subunit I messenger RNA in placentas from pregnancies complicated by preeclampsia. Acta Obstet Gynecol Scand. 2004;83(2):144–148.

    Article  PubMed  Google Scholar 

  21. Matsubara S, Minakami H, Sato I, Saito T. Decrease in cytochrome c oxidase activity detected cytochemically in the placental trophoblast of patients with pre-eclampsia. Placenta. 1997;18(4):255–259.

    Article  CAS  PubMed  Google Scholar 

  22. Wang Z, Zhang G, Lin M. Mitochondrial tRNA(leu) (UUR) gene mutation and the decreased activity of cytochrome c oxidase in preeclampsia. J Tongji Med Univ. 1999; 19(3):209–211.

    Article  CAS  PubMed  Google Scholar 

  23. Magann EF, Martin JN Jr. Twelve steps to optimal management of HELLP syndrome. Clin Obstet Gynecol. 1999;42(3): 532–550.

    Article  CAS  PubMed  Google Scholar 

  24. Martin JN Jr, Blake PG, Perry KG Jr, McCaul JF, Hess LW, Martin RW. The natural history of HELLP syndrome: patterns of disease progression and regression. Am J Obstet Gynecol. 1991;164(6 pt 1):1500–1509; ; discussion 1509–1513.

    Article  PubMed  Google Scholar 

  25. Ulrich-Merzenich G, Metzner C, Bhonde RR, Malsch G, Schiermeyer B, Vetter H. Simultaneous isolation of endothelial and smooth muscle cells from human umbilical artery or vein and their growth response to low-density lipoproteins. In Vitro Cell Dev Biol Anim. 2002;38(5):265–272.

    Article  PubMed  Google Scholar 

  26. Wanders RJ, Vreken P, den Boer ME, Wijburg FA, van Gennip AH, IJlst L. Disorders of mitochondrial fatty acyl-CoA beta-oxidation. J Inherit Metab Dis. 1999;22(4): 442–487.

    Article  CAS  PubMed  Google Scholar 

  27. Demaugre F, Bonnefont JP, Mitchell G, et al. Hepatic and muscular presentations of carnitine palmitoyl transferase deficiency: two distinct entities. Pediatr Res. 1988; 24(3):308–311.

    Article  CAS  PubMed  Google Scholar 

  28. Das AM. Regulation of mitochondrial ATP synthase activity in human myocardium. Clin Sci (Lond). 1998;94(5):499–504.

    Article  CAS  PubMed  Google Scholar 

  29. Srere PA. Citrate synthase. EC 4.1.3.7. Citrate oxaloacetatelyase (CoA-acetylation). In: Colowich SP, Kaplan NO, eds. Methods Enzymology XIII. New York. Academic Press; 1969;3–11.

    Google Scholar 

  30. Das AM, von Harlem R, Feist M, Lucke T, Kohlschutter A. Altered levels of high-energy phosphate compounds in fibroblasts from different forms of neuronal ceroid lipofuscinoses: further evidence for mitochondrial involvement. Eur J Paediatr Neurol. 2001;5(suppl A):143–146.

    Article  PubMed  Google Scholar 

  31. Chace DH, Kalas TA, Naylor EW. Use of tandem mass spectrometry for multianalyte screening of dried blood specimens from newborns. Clin Chem. 2003;49(11):1797–1817.

    Article  CAS  PubMed  Google Scholar 

  32. Vuorinen K, Remes A, Sormunen R, Tapanainen J, Hassinen IE. Placental mitochondrial DNA and respiratory chain enzymes in the etiology of preeclampsia. Obstet Gynecol. 1998;91(6):950–955.

    CAS  PubMed  Google Scholar 

  33. Yulug E, Yenilmez E, Unsal MA, Aydin S, Tekelioglu Y, Arvas H. Apoptotic and morphological features of the umbilical artery endothelium in mild and severe pre-eclampsia. Acta Obstet Gynecol Scand. 2006;85(9):1038–1045.

    Article  PubMed  Google Scholar 

  34. Scarpulla RC. Nuclear control of respiratory chain expression by nuclear respiratory factors and PGC-1-related coactivator. Ann N Y Acad Sci. 2008;1147:321–334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ventura FV, Ruiter JP, Ijlst L, de Almeida IT, Wanders RJ. Inhibitory effect of 3-hydroxyacyl-CoAs and other long-chain fatty acid beta-oxidation intermediates on mitochondrial oxidative phosphorylation. J Inherit Metab Dis. 1996; 19(2):161–164.

    Article  CAS  PubMed  Google Scholar 

  36. ter Veld F, Primassin S, Hoffmann L, Mayatepek E, Spiekerkoetter U. Corresponding increase in long-chain acyl-CoA and acylcarnitine after exercise in muscle from VLCAD mice. J Lipid Res. 2009;50(8):1556–1562.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Koumantakis E, Sifakis S, Koumantaki Y, et al. Plasma carnitine levels of pregnant adolescents in labor. J Pediatr Adolesc Gynecol. 2001;14(2):65–69.

    Article  CAS  PubMed  Google Scholar 

  38. Oey NA, van Vlies N, Wijburg FA, Wanders RJ, Attie-Bitach T, Vaz FM. l-Carnitine is synthesized in the human fetal-placental unit: potential roles in placental and fetal metabolism. Placenta. 2006;27(8):841–846.

    Article  CAS  PubMed  Google Scholar 

  39. Rytting E, Audus KL. Effects of low oxygen levels on the expression and function of transporter OCTN2 in BeWo cells. J Pharm Pharmacol. 2007;59(8):1095–1102.

    Article  CAS  PubMed  Google Scholar 

  40. Slaghekke F, Dekker G, Jeffries B. Endogenous inhibitors of nitric oxide and preeclampsia: a review. J Matern Fetal Neonatal Med. 2006;19(8):447–452.

    Article  CAS  PubMed  Google Scholar 

  41. Knapen MF, Peters WH, Mulder TP, Merkus HM, Jansen JB, Steegers EA. Glutathione and glutathione-related enzymes in decidua and placenta of controls and women with pre-eclampsia. Placenta. 1999;20(7):541–546.

    Article  CAS  PubMed  Google Scholar 

  42. Teran E, Vivero S, Racines-Orbe M, et al. Coenzyme Q10 is increased in placenta and cord blood during preeclampsia. Biofactors. 2005;25(1–4):153–158.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Carl-Neuberg Str. 1, 30625, Germany

    Sabine Illsinger MD, Nils Janzen MD, Karl-Heinz Schmidt, Jolanthe Bednarczyk, Lisa Mallunat, Julia Bode, Friederike Hagebölling, Thomas Lücke MD, PhD & Anibh M. Das MD, PhD

  2. Institute of Biometrics, Hannover Medical School, Hannover, Germany

    Ludwig Hoy PhD

  3. Department of Biochemistry and Tumor Lab, Clinic of Obstetrics and Gynecology, Hannover Medical School, Hannover, Germany

    Ralf Hass PhD

  4. Screening-Laboratory Hannover, Hannover, Germany

    Nils Janzen MD & Stefanie Sander MD

Authors
  1. Sabine Illsinger MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nils Janzen MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stefanie Sander MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Karl-Heinz Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jolanthe Bednarczyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lisa Mallunat
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Julia Bode
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Friederike Hagebölling
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ludwig Hoy PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Thomas Lücke MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ralf Hass PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Anibh M. Das MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sabine Illsinger MD.

Additional information

The work was done at the Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, 30625 Hannover, Germany.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Illsinger, S., Janzen, N., Sander, S. et al. Preeclampsia and HELLP Syndrome: Impaired Mitochondrial Function in Umbilical Endothelial Cells. Reprod. Sci. 17, 219–226 (2010). https://doi.org/10.1177/1933719109351597

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1177/1933719109351597

Key words

Search

Navigation