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Altered proteome profiles in maternal plasma in pregnancies with fetal growth restriction

Abstract

Fetal growth restriction (FGR) affects 3–5% of pregnancies and is associated with increased perinatal morbidity and mortality. Currently, there is no reliable biochemical test to differentiate a pathological FGR from a nonpathological one. The objective of this study was to screen whole maternal plasma to identify differentially expressed relatively abundant proteins associated with FGR. We analyzed maternal plasma from FGR (n=28) and healthy (n=22) pregnancies using two-dimensional gel electrophoresis (2D-GE) followed by software image analysis. Three spots with molecular weight (Mr) 18 kDa corresponding to haptoglobin (hp) α2, as identified by LC-MS/MS and immunoblotting, showed differential expression patterns in FGR. The distribution of hp α2 variants in maternal plasma samples showed the hp α2 variant 1 was low in 72% of FGR, medium in 16%, whereas high in 12%. In comparison, hp α2 variant 1 was high in (41%) of controls, medium in 41%, and low in 18% of cases. Based on the software image analysis, the mean spot volume for hp α2 variant 1 was 0.12 (SD=0.18) for FGR compared to 0.26 (SD=0.19) for control (p=0.006). Given that hp turnover is indicative of its maturation process and is traceable in plasma by its dominant/suppressed variants, we propose that hp α2 is an important potential target for evaluation of its clinical and pathophysiological role and as a diagnostic biomarker in FGR.

References

  1. 1.

    Cetin, I., Foidart, J. M., and Miozzo, M., et al. (2004) Fetal growth restriction: a workshop report.Placenta 25, 753–757.

  2. 2.

    Resnik, R. (2002) Intrauterine growth restriction.Obstet. Gynecol. 99, 490–496.

  3. 3.

    Jarvis, S., Glinianaia, S. V., Torrioli, M. G., et al. (2003) Cerebral palsy and intrauterine growth in single births: European collaborative study.Lancet 362, 1106–1111.

  4. 4.

    Barker, D. J. (2004) The developmental origins of well-being.Philos. Trans. R. Soc. Lond. B. Biol. Sci. 359, 1359–1366.

  5. 5.

    Jornayvaz, F. R., Selz, R., Tappy, L., and Theintz, G. E. (2004) Metabolism of oral glucose in children born small for gestational age: evidence for an impaired whole body glucose oxidation.Metabolism 53, 847–851.

  6. 6.

    Abdo, M., Irving, B., Hudson, P., and Zola, H. (2005) Development of a cluster of differentiation antibody-based protein microarray.J. Immunol. Methods 305, 3–9.

  7. 7.

    Abdolkhaleg D, Behrooz S. (2005) A sensitive immunoblotting method for screening of microalbuminuria in diabetic patients’ urine.Saudi Med J 26(7), 1075–1079.

  8. 8.

    Ergaz, Z., Avgil, M., and Ornoy, A. (2005) Intrauterine growth restriction-etiology and consequences: what do we know about the human situation and experimental animal models?Reprod. Toxicol. 20, 301–322.

  9. 9.

    Wilhelm, D., Mansmann, U., Neudeck, H., Matejevic, D., Vetter, K., and Graf, R. (2002) Decrease of elastic tissue fibres in stem villus blood vessels of the human placenta during IUGR and IUGR with concomitant preeclampsia.Anat. Embryol. (Berl) 205, 393–400.

  10. 10.

    Sibley, C. P., Turner, M. A., Cetin, I., et al. (2005) Placental phenotypes of intrauterine growth.Pediatr. Res. 58, 827–832.

  11. 11.

    Quero, C., Colome, N., Prieto, M. R., et al. (2004) Determination of protein markers in human serum: Analysis of protein expression in toxic oil syndrome studies.Proteomics 4, 303–315.

  12. 12.

    Crameri, R. (2005) The potential of proteomics and peptidomics for allergy and asthma research.Allergy 60, 1227–1237.

  13. 13.

    Davidsson, P. and Sjogren, M. (2005) The use of proteomics in biomarker discovery in neurodegenerative diseases.Dis. Markers 21, 81–92.

  14. 14.

    Shankar, R., Gude, N., Cullinane, F., Brennecke, S., Purcell, A. W., and Moses, E. K. (2005) An emerging role for comprehensive proteome analysis in human pregnancy research.Reproduction 129, 685–696.

  15. 15.

    Gaziano, E. P. (1995) Antenatal ultrasound and fetal Doppler. Diagnosis and outcome in intrauterine growth retardation.Clin. Perinatol. 22, 111–140.

  16. 16.

    Arbuckle, T. E., Wilkins, R., and Sherman, G. J. (1993) Birth weight percentiles by gestational age in Canada. Obstet. Gynecol.81, 39–48.

  17. 17.

    Gelbaya, T. A. and Nardo, L. G. (2005) Customised fetal growth chart: a systematic review.J. Obstet. Gynaecol. 25, 445–450.

  18. 18.

    Barkehall-Thomas, A., Wilson, C., Baker, L., ni Bhuinneain, M., and Wallace, E. M. (2005) Uterine artery Doppler velocimetry for the detection of adverse obstetric outcomes in patients with elevated mid-trimester beta-human chorionic gonadotrophin.Acta. Obstet. Gynecol. Scand. 84, 743–747.

  19. 19.

    Perkins, D. N., Pappin, D. J., Creasy, D. M., and Cottrell, J. S. (1999) Probability-based protein identification by searching sequence databases using mass spectrometry data.Electrophoresis 20, 3551–3567.

  20. 20.

    Hobbins, J. (1997) Morphometry of fetal gowth.Acta. Paediatr. Suppl. 423, 165–169.

  21. 21.

    Baschat, A. A. and Hecher, K. (2004) Fetal growth restriction due to placental disease.Semin. Perinatol. 28, 67–80.

  22. 22.

    Rutland, C. S., Mukhopadhyay, M., Underwood, S., Clyde, N., Mayhew, T. M., and Mitchell, C. A. (2005) Induction of intrauterine growth restriction by reducing placental vascular growth with the angioinhibin TNP-470.Biol. Reprod. 73, 1164–1173.

  23. 23.

    Tjoa, M. L., Oudejans, C. B., van Vugt, J. M., Blankenstein, M. A., and van Wijk, I. J. (2004) Markers for presymptomatic prediction of preeclampsia and intrauterine growth restriction.Hypertens. Pregnancy 23, 171–189.

  24. 24.

    Jain, S. K., Shah, M., Ransonet, L., Wise, R., and Bocchini, J. A., Jr. (1995) Maternal and neonatal plasma transthyretin (prealbumin) concentrations and birth weight of newborn infants.Biol. Neonate 68, 10–14.

  25. 25.

    Tommaselli, G. A., Pighetti, M., Nasti, A., et al. (2004) Serum leptin levels and uterine doppler flow velocimetry at 20 weeks’ gestation as markers for the development of preeclampsia.Gynecol. Endocrinol. 19, 160–165.

  26. 26.

    Krantz, D., Goetzl, L., Simpson, J. L., et al. (2004) Association of extreme first-trimester free human chorionic gonadotropin-beta, pregnancy-associated plasma protein A, and nuchal translucency with intrauterine growth restriction and other adverse pregnancy outcomes.Am. J. Obstet. Gynecol. 191, 1452–1458.

  27. 27.

    Roig, M. D., Sabria, J., Valls, C., et al. (2005) The use of biochemical markers in prenatal diagnosis of intrauterine growth retardation: insulin-like growth factor I, Leptin, and alphafetoprotein.Eur. J. Obstet. Gynecol. Reprod. Biol. 120, 27–32.

  28. 28.

    Ilagan, J. G., Stamilio, D. M., Ural, S. H., Macones, G. A., and Odibo, A. O. (2004) Abnormal multiple marker screens are associated with adverse perinatal outcomes in cases of intrauterine growth restriction.Am J Obstet. Gynecol. 191, 1465–1469.

  29. 29.

    Granger, J., Siddiqui, J., Copeland, S., and Remick, D. (2005). Albumin depletion of human plasma also removes low abundance proteins including the cytokines.Proteomics 5, 4713–4718.

  30. 30.

    Wang, H., Clouthier, S. G., Galchev, V., et al. (2005) Intact-protein-based high-resolution three-dimensional quantitative analysis system for proteome profiling of biological fluids.Mol. Cell. Proteomics 4, 618–625.

  31. 31.

    Pieper, R., Su, Q., Gatlin, C. L., Huang, S. T., Anderson, N. L., and Steiner, S. (2003) Multicomponent immunoaffinity subtraction chromatography: an innovative step towards a comprehensive survey of the human plasma proteome.Proteomics 3, 422–432.

  32. 32.

    Zolotarjova, N., Martosella, J., Nicol, G., Bailey, J., Boyes, B. E., and Barrett, W. C. (2005) Differences among techniques for high-abundant protein depletion.Proteomics 5, 3304–3313.

  33. 33.

    Koller, A., Washburn, M. P., Lange, B. M., et al. (2002) Proteomic survey of metabolic pathways in rice.Proc. Natl. Acad. Sci. USA 99, 11,969–11,974.

  34. 34.

    Person, M. D., Shen, J., Traner, A., et al. (2006) Protein fragment domains identified using 2D gel electrophoresis/MALDI-TOF.J. Biomol. Tech. 17, 145–156.

  35. 35.

    Mikkat, S., Koy, C., Ulbrich, M., Ringel, B., and Glocker, M. O. (2004) Mass spectrometric protein structure characterization reveals cause of migration differences of haptoglobin alpha chains in two-dimensional gel electrophoresis.Proteomics 4, 3921–3932.

  36. 36.

    John, H. A. and Purdom, I. F. (1989). Elevated plasma levels of haptoglobin in Duchenne muscular dystrophy: electrophoretic variants in patients with a severe form of the disease.Electrophoresis 10, 489–493.

  37. 37.

    Haram, K., Augensen, K., and Elsayed, S. (1983) Serum protein pattern in normal pregnancy with special reference to acute-phase reactants.Br. J. Obstet. Gynaecol. 90, 139–145.

  38. 38.

    Gatzka, C., Bremerich, D., Kaufmann, M., and Ahr, A. (2002) Isolated decrease of haptoglobin during pregnancy: diagnosis by chance or pathological?.Zentralbl. Gynakol. 124, 120–122.

  39. 39.

    Ahmed, N., Barker, G., Oliva, K. T., et al. (2004) Proteomic-based identification of haptoglobin-1 precursor as a novel circulating biomarker of ovarian cancer.Br. J. Cancer 91, 129–140.

  40. 40.

    Ahmed, N., Oliva, K. T., Barker G, et al. (2005) Proteomic tracking of serum protein isoforms as screening biomarkers of ovarian cancer.Proteomics 5, 4625–4636.

  41. 41.

    Sarioglu, H., Lottspeich, F., Walk, T., Jung, G., and Eckerskorn, C. (2000) Deamidation as a widespread phenomenon in two-dimensional polyacrylamide gel electrophoresis of human blood plasma proteins.Electrophoresis 21, 2209–2218.

  42. 42.

    Robinson, N. E. and Robinson, A. B. (2001) Deamidation of human proteins.Proc. Natl. Acad. Sci. USA 98, 12,409–12,413.

  43. 43.

    Robinson, N. E. and Robinson, A. B. (2001) Molecular clocks.Proc. Natl. Acad. Sci. USA 98, 944–949.

  44. 44.

    Bresalier, R. S., Byrd, J. C., Tessler, D., et al. (2004) A circulating ligand, for galectin-3 is a haptoglobin-related glycoprotein elevated in individuals with colon cancer.Gastroenterology 127, 741–748.

  45. 45.

    Ueda, K., Yamamasu, S., Nakamura, Y., et al. (2001) Involvement of phenotypes and serum levels of haptoglobin in the outcome of in vitro fertilization and embryo transfer.Gynecol. Obstet. Invest. 51, 219–222.

  46. 46.

    Herrler, A., von Wolff, M., and Beier, H. M. (2002) Proteins in the extraembryonic matrix of preimplantation rabbit embryos.Anat. Embryol. (Berl) 206, 49–55.

  47. 47.

    Berkova, N., Lemay, A., Dresser, D. W., Fontaine, J. Y., Kerizit, J., and Goupil, S. (2001) Haptoglobin is present in human endometrium and shows elevated levels in the decidua during pregnancy.Mol. Hum. Reprod. 7, 747–754.

  48. 48.

    Wilke, G., Rath, W., Schutz, E., Armstrong, V. W., and Kuhn, W. (1992). Haptoglobin as a sensitive marker of hemolysis in HELLP-syndrome.Int. J. Gynaecol. Obstet. 39, 29–34.

  49. 49.

    Raijmakers, M. T., Roes, E. M., te Morsche, R. H., Steegers, E. A., and Peters, W. H. (2003) Haptoglobin and its association with the HELLP syndrome.J. Med. Genet. 40, 214–216.

  50. 50.

    Yamamoto, H., Nishikawa, S., Yamazaki, K., and Kudo, R. (2000) Efficacy of haptoglobin administration in the early postoperative course of patients with a diagnosis of HELLP syndrome.J. Obstet. Gynaecol. 20, 610–611.

  51. 51.

    Cid, M. C., Grant, D. S., Hoffman, G. S., Auerbach, R., Fauci, A. S., and Kleinman, H. K. (1993) Identification of haptoglobin as an angiogenic factor in sera from patients with systemic vasculitis.J. Clin. Invest. 91, 977–985.

  52. 52.

    Dobryszycka, W. (1997) Biological functions of haptoglobin: new pieces to an old puzzle.Eur. J. Clin. Chem. Clin. Biochem. 35, 647–654.

  53. 53.

    de Kleijn, D. P., Smeets, M. B., Kemmeren, P. P., et al. (2002) Acute-phase protein haptoglobin is a cell migration factor involved in arterial restructuring.FASEB J 16, 1123–1125.

  54. 54.

    Rapkiewicz, A. V., Espina, V., Petricoin, E. F., 3rd, and Liotta, L. A. (2004) Biomarkers of ovarian tumours.Eur. J. Cancer 40, 2604–2612.

  55. 55.

    Elliott, H. G., Elliott, M. A., Watson, J., Steele, L., and Smith, K. D. (1995) Chromatographic investigation of the glycosylation pattern of alpha-1-acid glycoprotein secreted by the HepG2 cell line; a putative model for inflammation?Biomed. Chromatogr. 9, 199–204.

  56. 56.

    Popovici, R. M., Lu, M., Bhatia, S., Faessen, G. H., Giaccia, A. J., and Giudice, L. C. (2001) Hypoxia regulates insulin-like growth factor-binding protein 1 in human fetal hepatocytes in primary culture: suggestive molecular mechanisms for in utero fetal growth restriction caused by uteroplacental insufficiency.J. Clin. Endocrinol. Metab. 86, 2653–2659.

  57. 57.

    Choi, K. S., Song, L., Park, Y. M., et al. (2006) Analysis of human plasma proteome by 2DE-and 2D nanoLC-based mass spectrometry.Prep. Biochem. Biotechnol. 36, 3–17.

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Correspondence to Madhulika B. Gupta.

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Keywords

  • Retinol Binding Protein
  • Fetal Growth Restriction
  • Maternal Plasma
  • HELLP Syndrome
  • Placental Insufficiency