scholarly journals Prenatal lead exposure is associated with decreased cord blood DNA methylation of the glycoprotein VI gene involved in platelet activation and thrombus formation

2015 ◽  
Vol 1 (1) ◽  
pp. dvv007 ◽  
Author(s):  
Karin Engström ◽  
Filip Rydbeck ◽  
Maria Kippler ◽  
Tomasz K. Wojdacz ◽  
Shams Arifeen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Platelet Activation ◽  
Lead Exposure ◽  
Thrombus Formation ◽  
Glycoprotein Vi ◽  
Prenatal Lead Exposure

scholarly journals Prenatal lead exposure and cord blood DNA methylation in PROGRESS: an epigenome-wide association study

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Jonathan A Heiss ◽  
Martha M Téllez-Rojo ◽  
Guadalupe Estrada-Gutiérrez ◽  
Lourdes Schnaas ◽  
Chitra Amarasiriwardena ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Gestational Age ◽  
Lead Exposure ◽  
Inductively Coupled Plasma ◽  
Maternal Education ◽  
Association Studies ◽  
Mode Of Delivery ◽  
Underlying Mechanisms ◽  
Prenatal Lead Exposure

Abstract The effects of prenatal lead exposure on child development include impaired growth and cognitive function. DNA methylation might be involved in the underlying mechanisms and previous epigenome-wide association studies reported associations between lead exposure during pregnancy and cord blood methylation levels. However, it is unclear during which developmental stage lead exposure is most harmful. Cord blood methylation levels were assayed in 420 children from a Mexican pre-birth cohort using the Illumina Infinium MethylationEPIC microarray. Lead concentrations were measured in umbilical cord blood as well as in blood samples from the mothers collected at 2nd and 3rd trimester and delivery using inductively coupled plasma-mass spectrometry. In addition, maternal bone lead levels were measured in tibia and patella using X-ray fluorescence. Comprehensive quality control and preprocessing of microarray data was followed by an unbiased restriction to methylation sites with substantial variance. Methylation levels at 202 111 cytosine-phosphate-guanine sites were regressed on each exposure adjusting for child sex, leukocyte composition, batch variables, gestational age, birthweight-for-gestational-age, maternal age, maternal education and mode of delivery. We find no association between prenatal lead exposure and cord blood methylation. This null result is strengthened by a sensitivity analysis showing that in the same dataset known biomarkers for birthweight-for-gestational-age can be recovered and the fact that phenotypic associations with lead exposure have been described in the same cohort.

scholarly journals Prenatal lead exposure, telomere length in cord blood and DNA methylation age in the PROGRESS cohort

2021 ◽  
Vol 2021 (1) ◽  
Author(s):  
Jose Francisco Herrera Moreno ◽  
Haotian Wu ◽  
Tessa R. Bloomquist ◽  
Maria José Rosa ◽  
Allan C. Just ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Telomere Length ◽  
Lead Exposure ◽  
Dna Methylation Age ◽  
Prenatal Lead Exposure

An Epigenome-Wide Association Study for Prenatal Lead Exposure and Umbilical Cord Blood DNA Methylation in Project Viva

2018 ◽  
Vol 2017 (1) ◽  
pp. 129
Author(s):  
Shaowei Wu ◽  
Marie-France Hivert ◽  
Andres Cardenas ◽  
Jia Zhong ◽  
Sheryl L. Rifas-Shiman ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Association Study ◽  
Umbilical Cord ◽  
Umbilical Cord Blood ◽  
Lead Exposure ◽  
Prenatal Lead Exposure

Prenatal lead exposure, telomere length in cord blood, and DNA methylation age in the PROGRESS prenatal cohort

2021 ◽  
pp. 112577
Author(s):  
José F. Herrera-Moreno ◽  
Guadalupe Estrada-Gutierrez ◽  
Haotian Wu ◽  
Tessa R. Bloomquist ◽  
Maria José Rosa ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Telomere Length ◽  
Lead Exposure ◽  
Dna Methylation Age ◽  
Prenatal Lead Exposure

Prenatal lead exposure and cord blood DNA methylation in the Korean Exposome Study

2021 ◽  
Vol 195 ◽  
pp. 110767
Author(s):  
Jaehyun Park ◽  
Jeeyoung Kim ◽  
Esther Kim ◽  
Woo Jin Kim ◽  
Sungho Won
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Lead Exposure ◽  
Prenatal Lead Exposure

Identification of novel downstream targets of platelet glycoprotein VI activation by differential proteome analysis: implications for thrombus formation

Blood ◽  
2010 ◽  
Vol 115 (20) ◽  
pp. 4102-4110 ◽  
Author(s):  
Christian Schulz ◽  
Nina V. Leuschen ◽  
Thomas Fröhlich ◽  
Michael Lorenz ◽  
Susanne Pfeiler ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Membrane Trafficking ◽  
Thrombus Formation ◽  
Multivesicular Body ◽  
Platelet Glycoprotein ◽  
Body Protein ◽  
Glycoprotein Vi ◽  
Differentially Abundant Proteins ◽  
Platelet Proteins

Abstract Platelets play a key role in hemostasis and various diseases including arterial thrombosis. Glycoprotein VI (GPVI) mediates adhesion to collagen structures exposed at sites of vascular injury and subsequent platelet activation. We determined the effects of specific activation of GPVI on the human platelet proteome. Isolated human platelets were stimulated with an activating monoclonal antibody specific for GPVI. Platelet proteins were analyzed by 2-dimensional difference gel electrophoresis (2D-DIGE) and mass spectrometry. We identified 8 differentially abundant proteins associated with cell signaling, metabolism, organization and rearrangement of the cytoskeleton, and membrane trafficking. Differentially abundant proteins included aldose reductase (AR), beta-centractin, charged multivesicular body protein 3, Src substrate cortactin, ERp57, and pleckstrin. Importantly, GPVI-modulated protein abundance was functionally relevant. Correspondingly, AR enzyme activity significantly increased upon GPVI activation and inhibition of AR resulted in reduced platelet aggregation. Furthermore, ERp57 was released upon ligation of platelet GPVI and increased the activity of tissue factor, a major initiator of blood coagulation. In summary, GPVI activation results in differential changes in abundance of platelet proteins, including AR and ERp57, which support platelet aggregation and platelet-dependent coagulation. These results provide further insight into the mechanisms that underlie platelet activation through the GPVI receptor and may help to identify novel pharmacologic targets.

scholarly journals In-depth PtdIns(3,4,5)P3 signalosome analysis identifies DAPP1 as a negative regulator of GPVI-driven platelet function

2017 ◽  
Vol 1 (14) ◽  
pp. 918-932 ◽  
Author(s):  
Tom N. Durrant ◽  
James L. Hutchinson ◽  
Kate J. Heesom ◽  
Karen E. Anderson ◽  
Len R. Stephens ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Platelet Function ◽  
Binding Proteins ◽  
Thrombus Formation ◽  
Negative Regulator ◽  
Valuable Resource ◽  
Future Studies ◽  
Glycoprotein Vi ◽  
Key Points ◽  
Depth Analysis

Key Points We present the first in-depth analysis of platelet PtdIns(3,4,5)P3-binding proteins, providing a valuable resource for future studies. The PtdIns(3,4,5)P3-binding protein, DAPP1, negatively regulates glycoprotein VI–driven platelet activation and thrombus formation.

scholarly journals Diacylglycerol kinase ζ is a negative regulator of GPVI-mediated platelet activation

2019 ◽  
Vol 3 (7) ◽  
pp. 1154-1166 ◽  
Author(s):  
Alyssa J. Moroi ◽  
Nicole M. Zwifelhofer ◽  
Matthew J. Riese ◽  
Debra K. Newman ◽  
Peter J. Newman
Keyword(s):  
Platelet Activation ◽  
Bleeding Time ◽  
Thrombus Formation ◽  
Negative Regulator ◽  
Platelet Surface ◽  
Rotational Thromboelastometry ◽  
Surface Receptors ◽  
Glycoprotein Vi ◽  
Granule Secretion

Abstract Diacylglycerol kinases (DGKs) are a family of enzymes that convert diacylglycerol (DAG) into phosphatidic acid (PA). The ζ isoform of DGK (DGKζ) has been reported to inhibit T-cell responsiveness by downregulating intracellular levels of DAG. However, its role in platelet function remains undefined. In this study, we show that DGKζ was expressed at significant levels in both platelets and megakaryocytes and that DGKζ-knockout (DGKζ-KO) mouse platelets were hyperreactive to glycoprotein VI (GPVI) agonists, as assessed by aggregation, spreading, granule secretion, and activation of relevant signal transduction molecules. In contrast, they were less responsive to thrombin. Platelets from DGKζ-KO mice accumulated faster on collagen-coated microfluidic surfaces under conditions of arterial shear and stopped blood flow faster after ferric chloride–induced carotid artery injury. Other measures of hemostasis, as measured by tail bleeding time and rotational thromboelastometry analysis, were normal. Interestingly, DGKζ deficiency led to increased GPVI expression on the platelet and megakaryocyte surfaces without affecting the expression of other platelet surface receptors. These results implicate DGKζ as a novel negative regulator of GPVI-mediated platelet activation that plays an important role in regulating thrombus formation in vivo.

Mice lacking PECAM-1 and Ceacam1 have an aberrant platelet and thrombus phenotype

2021 ◽  
Author(s):  
Fahd Kuriri ◽  
Genia Burchall ◽  
Fehaid Alanazi ◽  
Juliana Antonipillai ◽  
Gasim Dobie ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Purinergic Receptors ◽  
Thrombus Formation ◽  
Surface Expression ◽  
Signalling Pathways ◽  
Double Knockout ◽  
In Vivo Models ◽  
Glycoprotein Vi ◽  
Microvascular Thrombosis

The immunoglobulin (Ig)–immunoreceptor tyrosine–based inhibitory motif (ITIM) bearing receptors, PECAM-1 and CEACAM1 have been shown net negative regulators of platelet-collagen interactions and hemi-ITAM signalling pathways. In this study, a double knockout (DKO) mouse was developed with deleted PECAM-1 and CEACAM1 to study their combined contribution in platelet activation by glycoprotein VI, C-type lectin-like receptor 2 (CLEC-2), protease activated receptor PAR-4, ADP purinergic receptors and thromboxane receptor TP A2 pathways. Additionally, their collective contribution was examined in thrombus formation under high shear and microvascular thrombosis using in vivo models. DKO platelets responded normally to ADP purinergic receptors and TP A2 pathway. However, DKO platelets released significantly higher amounts of P-selectin compared to hyper-responsive Pecam-1-/- or Ceacam1-/- versus wild-type (WT) upon stimulation with collagen related peptide or rhodocytin. Contrastingly, DKO platelets released increased amounts of P-selectin upon stimulation with PAR-4 agonist peptide or thrombin but not Pecam-1-/-, Ceacam1-/- or WT platelets. Blockade of phospholipase C (PLC) or Rho A kinase revealed that DKO platelets enhanced alpha granule release via PAR-4/Gαq/PLC signalling without crosstalk with Src/Syk or G12/13 signalling pathways. This DKO model showed a significant increase in thrombus formation compared to the hyper-responsive Ceacam1-/- or Pecam-1-/- versus WT phenotype. DKO platelets have similar glycoprotein surface expression compared to Pecam-1-/-, Ceacam1-/- and WT platelets. PECAM-1 and CEACAM1 work in concert to negatively regulate hemiITAM signalling, platelet-collagen interactions and PAR-4 Gαq protein coupled signalling pathways. Both PECAM-1 and CEACAM1 are required for negative regulation of platelet activation and microvascular thrombosis in vivo.

scholarly journals RhoG Protein Regulates Glycoprotein VI-Fc Receptor γ-Chain Complex-mediated Platelet Activation and Thrombus Formation

2013 ◽  
Vol 288 (47) ◽  
pp. 34230-34238 ◽  
Author(s):  
Soochong Kim ◽  
Carol Dangelmaier ◽  
Dheeraj Bhavanasi ◽  
Shu Meng ◽  
Hong Wang ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Thrombus Formation ◽  
Chain Complex ◽  
Fc Receptor ◽  
Glycoprotein Vi
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