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Aberrant Processing of Plasma Vitronectin and High Reproductive Sciences OnlineFirst, published on August 24, 2009 as doi:10.1177/1933719109342756 Aberrant Processing of Plasma Vitronectin and High-Molecular- Weight Kininogen Precedes the Onset of Preeclampsia Marion Blumenstein, PhD, Roneel Prakash, BSc, Garth J. S. Cooper, MD, PhD, and Robyn A. North, MD, PhD; for the SCOPE Consortium To date, there is no reliable test to identify women in early pregnancy at risk of developing preeclampsia. Difference gel electrophoresis (DIGE) identified the plasma proteins vitronectin (VN) and high- molecular-weight kininogen (HK) in association with preeclampsia. In a longitudinal proteomics study, the plasma of preeclamptic patients (n ¼ 6) was compared to healthy control participants (n ¼ 6) before the onset of preeclampsia (week 20) and at the time of presentation with clinical disease (weeks 33-36). The 75-kd single-chain VN molecule increased 1.6- to 1.9-fold in preeclampsia, whereas the 65-kd moiety of the 2-chain VN molecule decreased 1.5- to 1.7-fold compared to healthy controls (P < .05). Immunoblots revealed differences in proteolytic processing of VN and/or HK in women who develop preeclampsia or preeclampsia further complicated by small-for-gestational-age. Vitronectin and HK may prove to be useful as early markers of fibrinolytic activity and neutrophil activation, which are known to be associated with preeclampsia. KEY WORDS: Preeclampsia, small-for-gestational-age, difference in gel electrophoresis, plasma, vitronectin, high molecular weight kininogen. INTRODUCTION Inadequate trophoblast invasion and abnormal remodel- ing of spiral arteries during early placentation are believed Preeclampsia is a serious multisystem disorder, unique to to be initiating events.2 As a consequence of reduced human pregnancy. The rapidly progressing syndrome is uteroplacental blood flow and placental hypoxia, factors characterized by the development of maternal hyperten- are released by the placenta into the maternal circulation.3 sion and proteinuria, but in severe cases may result in sei- These factors trigger maternal vascular dysfunction, an zures, kidney failure, and liver dysfunction.1 The inflammatory response and enhanced coagulation, culmi- underlying pathophysiology of preeclampsia is complex. nating in this multisystem disorder.3 Furthermore, pree- clampsia is a recognized risk factor for the later development of cardiovascular disease and type 2 dia- From the School of Biological Sciences, Faculty of Science, University of betes, suggesting there is an underlying maternal meta- Auckland, Auckland, New Zealand (MB, GJSC); HortResearch, Auckland, bolic and vascular predisposition.4 New Zealand (RP); Medical Research Council Immunochemistry Unit, Department of Biochemistry, University of Oxford, United Kingdom (GJSC); Advances in proteomic technologies have enabled and Discipline of Obstetrics and Gynecology, School of Pediatrics and unbiased mapping of the plasma proteome to elucidate Reproductive Health, University of Adelaide, Australia (RAN). novel biological pathways that may contribute to disease Address correspondence to: Marion Blumenstein, PhD, School of Biological pathogenesis and toward a clinical marker set for pree- Sciences, The University of Auckland, 3a Symonds Street, Private Bag 92019, 5,6 Auckland, New Zealand. E-mail: [email protected]. clampsia. Here, we conducted a longitudinal proteo- mic study to identify preeclampsia-specific proteins in Reproductive Sciences Vol. 000 No. 00 Month 2009 1-9 DOI. 10.1177/1933719109342756 the maternal circulation. The study design was aimed at # 2009 The Author(s) identifying plasma proteins that were differentially 1 2 Reproductive Sciences Vol. 000, No. 00, Month 2009 Blumenstein et al expressed both in early pregnancy (week 20 of gestation) Preeclampsia was defined as systolic blood pressure when the women were apparently healthy and once pre- (BP) 140 mm Hg and/or diastolic BP 90 mm Hg eclampsia became clinically manifested (33-36 weeks’ on 2 or more occasions after 20 weeks’ gestation but prior gestation). Difference gel electrophoresis (DIGE) was to the onset of labor, or postpartum systolic BP 140 mm used to analyze EDTA plasma, depleted of the 6 most Hg and/or diastolic BP 90 mm Hg postpartum on at abundant proteins, from women who developed pree- least 2 occasions 4 hours apart, combined with either pro- clampsia and from matched healthy pregnant controls teinuria (spot protein to creatinine ratio 30 mg/mmol, who did not go on to develop the disease. or 24-hour urinary protein 0.3 g/24 h, or dipstick pro- Difference gel electrophoresis analysis of pregnancy teinuria 2þ), or any multiorgan complication.7 Severe plasma identified the glycoproteins vitronectin (VN) and preeclampsia was defined by the presence of 1 or more high-molecular-weight kininogen (HK) as being impli- of the following additional findings: coagulopathy, cated in the pathogenesis of preeclampsia. Follow-up hemolysis, hepatic impairment, acute renal insufficiency, immunoblots showed that women who developed pree- imminent eclampsia, or eclampsia. Small-for-gestational- clampsia alone appear to have a different expression pro- age was defined as a birth weight less than the tenth file of VN compared to women with preeclampsia customized centile (adjusted for infant sex and maternal complicated by small-for-gestational-age (SGA). Both ethnicity, height, and weight).8 patterns differed from that seen in early pregnancy plasma from normal pregnancy. Moreover, proteolytic process- ing of HK appears to be different in women who later Top 6 Depletion of Plasma developed preeclampsia and SGA but not in women with To remove the 6 most abundant proteins (albumin, trans- preeclampsia alone. ferrin, immunoglobulin G [IgG], IgA, haptoglobin, and a-1-antitrypsin), plasma was immunodepleted using the PATIENTS AND METHODS Multiple Affinity Removal System (MARS; Agilent, Santa Clara, California) according to the manufacturer’s Study Groups and Sample Collection instructions. Before depletion, complete protease inhibi- tor cocktail was added (Roche Applied Science, Auck- A longitudinal study was performed using DIGE analysis land, New Zealand). Depleted samples were buffer of plasma from nulliparous women recruited into the exchanged using 5 kd molecular weight cut-off centrifu- SCOPE study (SCreening fOr Pregnancy Endpoints, gal filters into 7 mol/L urea, 2 mol/L thiourea, and 1% Australian and New Zealand Clinical Trials Registry C7BzO detergent. Protein content was determined using ACTRN12607000551493). For each woman (n 6), ¼ the 2D Quant protein assay (GE Healthcare, Auckland, 2 time points were studied: (1) at week 20 of gestation New Zealand). prior to disease onset and (2) in the third trimester (weeks 33-36) after preeclampsia was diagnosed. Control partici- pants had a healthy pregnancy outcome and were sampled Difference Gel Electrophoresis Analysis of at week 20 and at weeks 33 to 36 (n ¼ 6) to provide Plasma matched controls for gestation at the time of disease onset. Study protocols were approved by the Auckland Depleted and buffer-exchanged plasma samples were Regional Ethics Committee (2000/157 and AKX/02/ labeled with 200 pmol per 50 mg of protein each with 00/364) and written informed consent was obtained from CyDye minimal dyes (GE Healthcare) according to the each woman. For immunoblot analysis, native plasma manufacturer’s protocol. For the pooled internal stan- from the women included in the DIGE study was used. dard, equal amounts of all preeclamptic cases and healthy Additional plasma at 20 þ 1 weeks’ gestation was obtained controls (n ¼ 6 each group) included in the experiment from women with subsequent preeclampsia and an SGA were combined. To minimize dye bias samples were baby (n ¼ 4) and healthy controls (n ¼ 4) for western blot labeled with Cy3 or Cy5 as follows: within each group analysis. Blood was collected into EDTA-tubes, centri- half of the controls were labeled with Cy3 and run on the fuged (2400g, 10 minutes at 4 C), and the plasma stored same gels with cases labeled with Cy5. The other half of at À80C. The mean time between specimen collection the controls were labeled with Cy5 and run with Cy3 and storage at –80C was 1.9 (SD 1.2) hours for cases and labeled cases. All gels included the internal standard, 1.7 (SD 0.6) hours for controls, P ¼ .74. labeled with Cy2. Aberrant Processing of Plasma Vitronectin Reproductive Sciences Vol. 000, No. 00, Month 2009 3 Immobilized pH gradient (IPG) strips (11 cm, pH University of Auckland. Tandem MS/MS data were 4-7) were rehydrated with a multiplexed plasma sample extracted from raw spectra using Mascot Distiller (Matrix comprising 50 mg protein for each CyDye-labeled case, Science, London, UK). Data were searched against the control, and the pooled internal standard in rehydration Swiss-Prot database (version 52.2, dated April 14, buffer (7 mol/L urea, 2 mol/L thiourea, 1% C7BzO 2007), using the Mascot search engine v2.2.0 with the detergent, 1% IPG Buffer pH 4-7, 65 mmol/L DTT, and following parameters—taxonomy: human, semitrypsin 0.002% bromophenol blue). First dimension separation cleavage with up to 1 missed cleavage allowed; fixed was performed on a Multiphor II flatbed (GE Healthcare) modification: propionamidation; variable modification: followed by sodium dodecyl sulfate polyacrylamide gel oxidation (M), mass tolerances + 0.1 d, peptide charges electrophoresis (SDS-PAGE), using Criterion 8% to 2þ and 3þ. Positive identifications reported here had at 16% Tris-HCl midigels
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