Hemopexin and α1-microglobulin heme scavengers with differential involvement in preeclampsia and fetal growth restriction

Hemopexin and α1-microglobulin act as scavengers to eliminate free heme-groups responsible for hemoglobin-induced oxidative stress. The present study evaluated maternal and fetal plasma concentrations of these scavengers in the different phenotypes of placenta-mediated disorders. Singleton pregnancies with normotensive fetal growth restriction [FGR] (n = 47), preeclampsia without FGR (n = 45) and preeclampsia with FGR (n = 51) were included prospectively as well as uncomplicated pregnancies (n = 49). Samples were collected at delivery and ELISA analysis was applied to measure the hemopexin and α1-microglobulin concentrations. In maternal blood in preeclampsia with and without FGR, hemopexin was significantly lower (p = 0.003 and p<0.001, respectively) and α1-microglobulin was significantly higher (p<0.001 in both) whereas no difference existed in normotensive FGR mothers compared to controls. In contrast, in fetal blood in growth restricted fetuses with and without preeclampsia, both hemopexin and α1-microglobulin were significantly lower (p<0.001 and p = 0.001 for hemopexin, p = 0.016 and p = 0.013 for α1-microglobulin, respectively) with no difference in fetuses from preeclampsia without FGR in comparison to controls. Thus, hemopexin and α1-microglobulin present significantly altered concentrations in maternal blood in the maternal disease -preeclampsia- and in cord blood in the fetal disease -FGR-, which supports their differential role in placenta-mediated disorders in accordance with the clinical presentation of these disorders.

[1]  V. Pergialiotis,et al.  The role of hemoglobin degradation pathway in preeclampsia: A systematic review and meta-analysis. , 2020, Placenta.

[2]  E. Jauniaux,et al.  The placenta , 2020, Oxford Textbook of Obstetrics and Gynaecology.

[3]  G. Antoni,et al.  Assessment of glucagon receptor occupancy by Positron Emission Tomography in non-human primates , 2019, Scientific Reports.

[4]  E. Gratacós,et al.  Distinctive patterns of placental lesions in pre‐eclampsia vs small‐for‐gestational age and their association with fetoplacental Doppler , 2019, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[5]  S. Hansson,et al.  Alpha-1 microglobulin as a potential therapeutic candidate for treatment of hypertension and oxidative stress in the STOX1 preeclampsia mouse model , 2019, Scientific Reports.

[6]  M. Walker,et al.  Potential biological therapies for severe preeclampsia: a systematic review and meta-analysis , 2019, BMC Pregnancy and Childbirth.

[7]  K. Räikkönen,et al.  Plasma Heme Scavengers Alpha-1-Microglobulin and Hemopexin as Biomarkers in High-Risk Pregnancies , 2019, Front. Physiol..

[8]  J. Vermeesch,et al.  Preeclampsia is Associated with Sex-Specific Transcriptional and Proteomic Changes in Fetal Erythroid Cells , 2019, International journal of molecular sciences.

[9]  B. Trénor,et al.  Optimization of Lead Placement in the Right Ventricle During Cardiac Resynchronization Therapy. A Simulation Study , 2019, Front. Physiol..

[10]  Jaap Keijer,et al.  Diet-Independent Correlations between Bacteria and Dysfunction of Gut, Adipose Tissue, and Liver: A Comprehensive Microbiota Analysis in Feces and Mucosa of the Ileum and Colon in Obese Mice with NAFLD , 2018, International journal of molecular sciences.

[11]  I. Crocker,et al.  Cell free hemoglobin in the fetoplacental circulation: a novel cause of fetal growth restriction? , 2018, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  M. Rincon,et al.  Evaluation of Hemolysis as a Severe Feature of Preeclampsia , 2018, Hypertension.

[13]  S. Hansson,et al.  The hemoglobin degradation pathway in patients with preeclampsia - Fetal hemoglobin, heme, heme oxygenase-1 and hemopexin - Potential diagnostic biomarkers? , 2018, Pregnancy hypertension.

[14]  E. Gratacós,et al.  Diagnosis and surveillance of late‐onset fetal growth restriction , 2018, American journal of obstetrics and gynecology.

[15]  Kamran Mansouri,et al.  Protective effect of Malva sylvestris L. extract in ischemia-reperfusion induced acute kidney and remote liver injury , 2017, PloS one.

[16]  J. Ranstam,et al.  Fetal hemoglobin in umbilical cord blood in preeclamptic and normotensive pregnancies: A cross-sectional comparative study , 2017, PloS one.

[17]  S. Hansson,et al.  Recombinant alpha-1-microglobulin: a potential treatment for preeclampsia. , 2017, Drug discovery today.

[18]  J. Ranstam,et al.  Fetal hemoglobin, α1-microglobulin and hemopexin are potential predictive first trimester biomarkers for preeclampsia. , 2016, Pregnancy hypertension.

[19]  S. Hansson,et al.  The Human Endogenous Protection System against Cell-Free Hemoglobin and Heme Is Overwhelmed in Preeclampsia and Provides Potential Biomarkers and Clinical Indicators , 2015, PloS one.

[20]  Ludovico Minati,et al.  Slow Breathing and Hypoxic Challenge: Cardiorespiratory Consequences and Their Central Neural Substrates , 2015, PloS one.

[21]  S. Hansson,et al.  A1M Ameliorates Preeclampsia-Like Symptoms in Placenta and Kidney Induced by Cell-Free Fetal Hemoglobin in Rabbit , 2015, PloS one.

[22]  P. Roche,et al.  Macropinocytosis in phagocytes: regulation of MHC class-II-restricted antigen presentation in dendritic cells , 2015, Front. Physiol..

[23]  S. Hansson,et al.  Oxidative stress in preeclampsia and the role of free fetal hemoglobin , 2015, Front. Physiol..

[24]  I. Sargent,et al.  IFPA Senior Award Lecture: making sense of pre-eclampsia - two placental causes of preeclampsia? , 2014, Placenta.

[25]  K. Maršál,et al.  A1M/α1-Microglobulin Protects from Heme-Induced Placental and Renal Damage in a Pregnant Sheep Model of Preeclampsia , 2014, PloS one.

[26]  E. Gratacós,et al.  Update on the Diagnosis and Classification of Fetal Growth Restriction and Proposal of a Stage-Based Management Protocol , 2014, Fetal Diagnosis and Therapy.

[27]  N. Rhind,et al.  DNA replication timing. , 2013, Cold Spring Harbor perspectives in biology.

[28]  P. Buehler,et al.  Cell-free hemoglobin and its scavenger proteins: new disease models leading the way to targeted therapies. , 2013, Cold Spring Harbor perspectives in medicine.

[29]  P. Buehler,et al.  Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins. , 2013, Blood.

[30]  Asad Malik,et al.  Maternal and fetal risk factors for stillbirth: population based study , 2013, BMJ.

[31]  B. Thilaganathan,et al.  Maternal cardiac function in preeclampsia , 2011, Current opinion in obstetrics & gynecology.

[32]  F. Vinchi,et al.  Haptoglobin and Hemopexin in Heme Detoxification and Iron Recycling , 2011 .

[33]  B. Thilaganathan,et al.  Fetal hemoglobin and α1-microglobulin as first- and early second-trimester predictive biomarkers for preeclampsia. , 2011, American journal of obstetrics and gynecology.

[34]  S. Hansson,et al.  Perfusion of human placenta with hemoglobin introduces preeclampsia-like injuries that are prevented by α1-microglobulin. , 2011, Placenta.

[35]  Francesc Figueras,et al.  Intrauterine growth restriction: new concepts in antenatal surveillance, diagnosis, and management. , 2011, American Journal of Obstetrics and Gynecology.

[36]  E. Steegers,et al.  Pre-eclampsia , 2010, The Lancet.

[37]  N. Morello,et al.  Heme scavenging and the other facets of hemopexin. , 2010, Antioxidants & redox signaling.

[38]  J. Larsson,et al.  Increased levels of cell-free hemoglobin, oxidation markers, and the antioxidative heme scavenger alpha(1)-microglobulin in preeclampsia. , 2010, Free radical biology & medicine.

[39]  Lelia Duley,et al.  The global impact of pre-eclampsia and eclampsia. , 2009, Seminars in perinatology.

[40]  Piero Carninci,et al.  Placental expression profiling in preeclampsia: local overproduction of hemoglobin may drive pathological changes. , 2008, Fertility and sterility.

[41]  F. Figueras,et al.  Reference ranges for uterine artery mean pulsatility index at 11–41 weeks of gestation , 2008, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[42]  H. Bunn New agents that stimulate erythropoiesis. , 2007, Blood.

[43]  P. Højrup,et al.  Identification of the receptor scavenging hemopexin-heme complexes. , 2005, Blood.

[44]  A. Baschat,et al.  The cerebroplacental Doppler ratio revisited , 2003, Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology.

[45]  L. Lögdberg,et al.  alpha(1)-Microglobulin: a yellow-brown lipocalin. , 2000, Biochimica et biophysica acta.

[46]  J. Enghild,et al.  α1‐Microglobulin chromophores are located to three lysine residues semiburied in the lipocalin pocket and associated with a novel lipophilic compound , 1999, Protein science : a publication of the Protein Society.

[47]  U. Muller-eberhard,et al.  The type II hemopexin interleukin-6 response element predominates the transcriptional regulation of the hemopexin acute phase responsiveness. , 1995, Biochemical and biophysical research communications.

[48]  F. P. Hadlock,et al.  Estimation of fetal weight with the use of head, body, and femur measurements--a prospective study. , 1985, American journal of obstetrics and gynecology.

[49]  J. Fleming,et al.  A CRITICAL EVALUATION OF SONAR “CROWN‐RUMP LENGTH” MEASUREMENTS , 1975, British journal of obstetrics and gynaecology.

[50]  J. H. Jandl,et al.  Factors influencing relative rates of synthesis of adult and fetal hemoglobin in vitro. , 1960, The Journal of clinical investigation.

[51]  A. Odutayo,et al.  The kidney in normal pregnancy and preeclampsia. , 2011, Seminars in nephrology.

[52]  G. Macones,et al.  Intrapartum Fetal Heart Rate Monitoring: Nomenclature, Interpretation, and General Management Principles , 2009 .

[53]  J Figueras,et al.  Customized birthweight standards for a Spanish population. , 2008, European journal of obstetrics, gynecology, and reproductive biology.

[54]  Domenico Arduini,et al.  Normal values of Pulsatility Index front fetal vessels: A cross-sectional study on 1556 healthy fetuses , 1990, Journal of perinatal medicine.