Abstract: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 = 6) was compared to healthy control participants (n = 6) before the onset of preeclampsia (week 20) and at the time of presentation with clinical disease (weeks 33-36). T… Show more
“…Cleavage of HK by plasma kallikrein results in kininogen heavy chain (63 kDa), light chain (58 kDa) and modified light chain (45 kDa). It has been reported that down-regulation of plasma HK precedes the onset of preeclampsia (20-week gestation) [44]. In agreement with these observations, we found that the kininogen modified light chain (45 kDa) was down-regulated in UCS of IUGR newborns.…”
Section: Blood Pressure Alteration and Iugrsupporting
Foetal growth is a result of a complex net of processes, requiring coordination within the maternal, placental, and foetal compartments, the imbalance or lack of which may lead to intrauterine growth restriction (IUGR). IUGR is the major cause of perinatal morbidity and mortality, and is also related to enhanced morbidity and metabolic abnormalities later in life. In the present study, the protein profiles of umbilical cord serum (UCS) and amniotic fluid (AF) of ten IUGR and ten appropriate for gestational age newborns have been analysed by 2-DE, and nanoHPLC-Chip/MS technology. A total of 18 and 13 spots were found to be differentially expressed (p<0.01) in UCS and AF respectively. The unique differentially expressed proteins identified by MS/MS analysis were 14 in UCS, and 11 in AF samples. Protein gene ontology classification indicate that 21% of proteins are involved in inflammatory response, 20% in immune response, while a smaller proportion are related to transport, blood pressure, and coagulation. These results support the conclusion that the IUGR condition alters the expression of proteins involved in the coagulation process, immune mechanisms, blood pressure and iron and copper homeostasis control, offering a new insight into IUGR pathogenesis.
“…Cleavage of HK by plasma kallikrein results in kininogen heavy chain (63 kDa), light chain (58 kDa) and modified light chain (45 kDa). It has been reported that down-regulation of plasma HK precedes the onset of preeclampsia (20-week gestation) [44]. In agreement with these observations, we found that the kininogen modified light chain (45 kDa) was down-regulated in UCS of IUGR newborns.…”
Section: Blood Pressure Alteration and Iugrsupporting
Foetal growth is a result of a complex net of processes, requiring coordination within the maternal, placental, and foetal compartments, the imbalance or lack of which may lead to intrauterine growth restriction (IUGR). IUGR is the major cause of perinatal morbidity and mortality, and is also related to enhanced morbidity and metabolic abnormalities later in life. In the present study, the protein profiles of umbilical cord serum (UCS) and amniotic fluid (AF) of ten IUGR and ten appropriate for gestational age newborns have been analysed by 2-DE, and nanoHPLC-Chip/MS technology. A total of 18 and 13 spots were found to be differentially expressed (p<0.01) in UCS and AF respectively. The unique differentially expressed proteins identified by MS/MS analysis were 14 in UCS, and 11 in AF samples. Protein gene ontology classification indicate that 21% of proteins are involved in inflammatory response, 20% in immune response, while a smaller proportion are related to transport, blood pressure, and coagulation. These results support the conclusion that the IUGR condition alters the expression of proteins involved in the coagulation process, immune mechanisms, blood pressure and iron and copper homeostasis control, offering a new insight into IUGR pathogenesis.
“…Review articles, studies that did not use proteomic techniques or studies that did not compare PE with a normotensive (control) group were excluded. Moreover, studies involving animals only, studies presenting protein m/z values only rather than protein identifications, or those studies that compared different proteomic approaches were further excluded, leaving 16 primary studies eligible for this review ( Watanabe et al , 2004 ; Vascotto et al , 2007 ; Buhimschi et al , 2008 ; Jin et al , 2008 ; Park et al , 2008 ; Blankley et al , 2009 ; Blumenstein et al , 2009a , b ; Centlow et al , 2010 ; Gharesi-Fard et al , 2010 ; Rasanen et al , 2010 ; Johnstone et al , 2011 ; Liu et al , 2011 ; Epiney et al , 2012 ; Kolla et al , 2012 ; Myers et al , 2013 ). Figure 1 Flowchart showing selection of studies included in the systematic review.…”
STUDY QUESTIONDo any proteomic biomarkers previously identified for pre-eclampsia (PE) overlap with those identified in women with polycystic ovary syndrome (PCOS).SUMMARY ANSWERFive previously identified proteomic biomarkers were found to be common in women with PE and PCOS when compared with controls.WHAT IS KNOWN ALREADYVarious studies have indicated an association between PCOS and PE; however, the pathophysiological mechanisms supporting this association are not known.STUDY DESIGN, SIZE, DURATIONA systematic review and update of our PCOS proteomic biomarker database was performed, along with a parallel review of PE biomarkers. The study included papers from 1980 to December 2013.PARTICIPANTS/MATERIALS, SETTING, METHODSIn all the studies analysed, there were a total of 1423 patients and controls. The number of proteomic biomarkers that were catalogued for PE was 192.MAIN RESULTS AND THE ROLE OF CHANCEFive proteomic biomarkers were shown to be differentially expressed in women with PE and PCOS when compared with controls: transferrin, fibrinogen α, β and γ chain variants, kininogen-1, annexin 2 and peroxiredoxin 2. In PE, the biomarkers were identified in serum, plasma and placenta and in PCOS, the biomarkers were identified in serum, follicular fluid, and ovarian and omental biopsies.LIMITATIONS, REASONS FOR CAUTIONThe techniques employed to detect proteomics have limited ability in identifying proteins that are of low abundance, some of which may have a diagnostic potential. The sample sizes and number of biomarkers identified from these studies do not exclude the risk of false positives, a limitation of all biomarker studies. The biomarkers common to PE and PCOS were identified from proteomic analyses of different tissues.WIDER IMPLICATIONS OF THE FINDINGSThis data amalgamation of the proteomic studies in PE and in PCOS, for the first time, discovered a panel of five biomarkers for PE which are common to women with PCOS, including transferrin, fibrinogen α, β and γ chain variants, kininogen-1, annexin 2 and peroxiredoxin 2. If validated, these biomarkers could provide a useful framework for the knowledge infrastructure in this area. To accomplish this goal, a well co-ordinated multidisciplinary collaboration of clinicians, basic scientists and mathematicians is vital.STUDY FUNDING/COMPETING INTEREST(S)No financial support was obtained for this project. There are no conflicts of interest.
“…Using a BK‐release assay, Mohamed et al compared five sites within placentas obtained from healthy and hypertensive pregnancies and found decreased LK and HK in PIH . Using western blot, Blumenstein et al detected decreased HK in the plasma from women with PE complicated by small for gestational age at 20 weeks of gestation compared with healthy controls . However, LC/MS/MS analysis of serum samples revealed that peptides mapping to KNG‐1 were increased in severe PE .…”
Section: Discussionmentioning
confidence: 99%
“…Early detection of PE can aid in reducing maternal mortalities . Several studies have discovered and validated PE biomarkers, including kininogen‐1 and high‐molecular weight kininogen (HK) and their proteolytic fragments/peptides …”
Section: Introductionmentioning
confidence: 99%
“…1,2 Several studies have discovered and validated PE biomarkers, including kininogen-1 and highmolecular weight kininogen (HK) and their proteolytic fragments/ peptides. [3][4][5][6][7][8][9] The kininogen-1 (KNG-1) gene is located on chromosome three.…”
Rationale
Studies identified kininogen as a potential biomarker of preeclampsia, a major cause of adverse maternal outcomes. High‐molecular‐weight kininogen (HK) and its activated form participate in numerous pathways associated with establishing and maintaining pregnancy. However, dynamic changes in HK and naturally occurring HK‐derived peptides during the natural course of pregnancy are largely unknown.
Methods
Longitudinal serum samples during the course of normal pregnancy (trimesters T1, T2, T3) from 60 pregnant women were analyzed by western blot with an anti‐HK antibody. Circulating peptides in longitudinal serum specimens derived from 50 participants were enriched using nanoporous silica thin films. Peptides were identified by liquid chromatography/tandem mass spectrometry (LC/MS/MS) and database searching. Relative quantification was performed using MaxQuant and in‐house scripts. Normality was evaluated by either ANOVA or Friedman tests with p < 0.05 for statistical significance.
Results
Western blotting revealed that HK significantly decreased during normal pregnancy (T1 vs T2, p < 0.05; T1 vs T3, p < 0.0001). A 100 kDa intermediate increased during pregnancy (T1 vs T2, p < 0.005; T1 vs T3, p < 0.01). Moreover, the heavy chain (T1 vs T2, p < 0.0001; T1 vs T3, p < 0.0001; T2 vs T3, p < 0.01) and light chain (T1 vs T2, p < 0.0001; T1 vs T3, p < 0.0001; T2 vs T3, p < 0.05) significantly increased during pregnancy. LC/MS/MS analysis identified 180 kininogen‐1 peptides, of which 167 mapped to domain 5 (D5). Seventy‐three peptides with ten or more complete data sets were included for further analysis. Seventy peptides mapped to D5, and 3, 24, and 43 peptides showed significant decrease, no trend, and significant increase, respectively, during pregnancy.
Conclusions
This study demonstrates dynamic changes in HK and naturally occurring HK‐derived peptides during pregnancy. Our study sheds light on the gestational changes of HK and its peptides for further validation of them as potential biomarkers for pregnancy‐related complications.
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