An intronic polymorphism in the PAR-1 gene is associated with platelet receptor density and the response to SFLLRN

Blood ◽  
2003 ◽  
Vol 101 (5) ◽  
pp. 1833-1840 ◽  
Author(s):  
Annabelle Dupont ◽  
Pierre Fontana ◽  
Christilla Bachelot-Loza ◽  
Jean-Luc Reny ◽  
Ivan Bièche ◽  
...  
Keyword(s):  
Allelic Frequency ◽  
Interindividual Variation ◽  
Expression Data ◽  
Receptor Density ◽  
Platelet Response ◽  
Platelet Surface ◽  
Mrna Expression Data ◽  
Intronic Polymorphism ◽  
Platelet Receptor ◽  
Protease Activated Receptor 1

Protease-activated receptor 1 (PAR-1), the main thrombin receptor on vascular cells, plays a key role in platelet activation. We examined the range of PAR-1 expression on platelets, obtained twice, 1 week apart, from 100 healthy subjects and found a 2-fold interindividual variation in receptor numbers (95% CI = 858-1700). Because PAR-1 density was stable with time (r2 = 76%,P < .001), we sought a genetic explanation for the observed variability. To validate this approach, we also analyzed the α2β1 genotype according to receptor density and platelet mRNA expression data. We found that the number of PAR-1 receptors on the platelet surface is associated with the intervening sequence IVSn−14 A/T intronic variation. The number of receptors was also found to govern the platelet response to the SFLLRN agonist, in terms of aggregation and P-selectin expression. The T allele (allelic frequency, 0.14) can be considered as an allele with decreased expression, because it was associated with lower PAR-1 expression on the platelet surface and with a lower response to SFLLRN. The IVSn−14 A/T intronic variation may therefore be clinically relevant.

scholarly journals Mechanisms of receptor shedding in platelets

Blood ◽  
2018 ◽  
Vol 132 (24) ◽  
pp. 2535-2545 ◽  
Author(s):  
Samantha J. Montague ◽  
Robert K. Andrews ◽  
Elizabeth E. Gardiner
Keyword(s):  
Current Knowledge ◽  
Membrane Properties ◽  
Receptor Regulation ◽  
Receptor Density ◽  
Receptor System ◽  
Platelet Surface ◽  
Platelet Receptor ◽  
A Cell ◽  
Receptor Shedding ◽  
Powerful Process

Abstract The ability to upregulate and downregulate surface-exposed proteins and receptors is a powerful process that allows a cell to instantly respond to its microenvironment. In particular, mobile cells in the bloodstream must rapidly react to conditions where infection or inflammation are detected, and become proadhesive, phagocytic, and/or procoagulant. Platelets are one such blood cell that must rapidly acquire and manage proadhesive and procoagulant properties in order to execute their primary function in hemostasis. The regulation of platelet membrane properties is achieved via several mechanisms, one of which involves the controlled metalloproteolytic release of adhesion receptors and other proteins from the platelet surface. Proteolysis effectively lowers receptor density and reduces the reactivity of platelets, and is a mechanism to control robust platelet activation. Recent research has also established clear links between levels of platelet receptors and platelet lifespan. In this review, we will discuss the current knowledge of metalloproteolytic receptor regulation in the vasculature with emphasis on the platelet receptor system to highlight how receptor density can influence both platelet function and platelet survival.

Streptokinase-induced platelet activation involves antistreptokinase antibodies and cleavage of protease-activated receptor-1

Blood ◽  
2000 ◽  
Vol 95 (4) ◽  
pp. 1301-1308 ◽  
Author(s):  
James P. McRedmond ◽  
Patrick Harriott ◽  
Brian Walker ◽  
Desmond J. Fitzgerald
Keyword(s):  
Platelet Aggregation ◽  
Platelet Activation ◽  
Cell Activation ◽  
Fc Receptor ◽  
Thrombin Inhibitor ◽  
Platelet Response ◽  
Intact Cells ◽  
Platelet Surface ◽  
Tethered Ligand ◽  
Protease Activated Receptor 1

Streptokinase activates platelets, limiting its effectiveness as a thrombolytic agent. The role of antistreptokinase antibodies and proteases in streptokinase-induced platelet activation was investigated. Streptokinase induced localization of human IgG to the platelet surface, platelet aggregation, and thromboxane A2production. These effects were inhibited by a monoclonal antibody to the platelet Fc receptor, IV.3. The platelet response to streptokinase was also blocked by an antibody directed against the cleavage site of the platelet thrombin receptor, protease-activated receptor-1 (PAR-1), but not by hirudin or an active site thrombin inhibitor, Ro46-6240. In plasma depleted of plasminogen, exogenous wild-type plasminogen, but not an inactive mutant protein, S741A plasminogen, supported platelet aggregation, suggesting that the protease cleaving PAR-1 was streptokinase-plasminogen. Streptokinase-plasminogen cleaved a synthetic peptide corresponding to PAR-1, resulting in generation of PAR-1 tethered ligand sequence and selectively reduced binding of a cleavage-sensitive PAR-1 antibody in intact cells. A combination of streptokinase, plasminogen, and antistreptokinase antibodies activated human erythroleukemic cells and was inhibited by pretreatment with IV.3 or pretreating the cells with the PAR-1 agonist SFLLRN, suggesting Fc receptor and PAR-1 interactions are necessary for cell activation in this system also. Streptokinase-induced platelet activation is dependent on both antistreptokinase-Fc receptor interactions and cleavage of PAR-1.

scholarly journals Normalization strategies for mRNA expression data in cartilage research

2008 ◽  
Vol 16 (8) ◽  
pp. 947-955 ◽  
Author(s):  
K. Fundel ◽  
J. Haag ◽  
P.M. Gebhard ◽  
R. Zimmer ◽  
T. Aigner
Keyword(s):  
Mrna Expression ◽  
Expression Data ◽  
Mrna Expression Data

scholarly journals PABPC1 relevant bioinformatic profiling and prognostic value in gliomas

2020 ◽  
Vol 16 (1) ◽  
pp. 4279-4288 ◽  
Author(s):  
Qiangwei Wang ◽  
Zhiliang Wang ◽  
Zhaoshi Bao ◽  
Chuanbao Zhang ◽  
Zheng Wang ◽  
...  
Keyword(s):  
Biological Process ◽  
The Cancer Genome Atlas ◽  
Analysis Tool ◽  
Expression Data ◽  
Clinical Value ◽  
Mrna Expression Data ◽  
R Language ◽  
Molecular Features ◽  
Cancer Genome Atlas ◽  
Genome Atlas

Aim: We aimed at investigating molecular features and potential clinical value of PABPC1 in gliomas. Materials & methods: We assembled totally 1000 glioma samples with mRNA expression data from Chinese Glioma Genome Atlas and The Cancer Genome Atlas. We utilized R language as the main analysis tool. Gene Ontology was performed for functional analysis. Results: PABPC1 was downregulated in gliomas with higher malignance and PABPC1 may contribute as potential predictor of proneural subtype in gliomas. Higher expression of PABPC1 was significantly related to better prognosis and related to biological process of translation. Conclusion: Our finding improves the understanding of PABPC1 as a novel biomarker with potential therapeutic connotations.

Dynamic Debonding Force Measurements of Ligand (RGD)-Platelet Receptor (GP Ilb/IIIa) System under Physiological Conditions

2000 ◽  
Vol 6 (S2) ◽  
pp. 974-975
Author(s):  
ImShik Lee ◽  
Roger E. Marchant
Keyword(s):  
Thrombus Formation ◽  
Peptide Sequence ◽  
Chain Extension ◽  
Force Measurements ◽  
Platelet Surface ◽  
Force Microscopy ◽  
Atomic Force ◽  
Direct Measurements ◽  
Platelet Receptor ◽  
Physical Absorption

ABSTRACTBinding formation between a peptide sequence (GSSSGRGDSPA) which contains the cell adhesion sequence –RGD-found in fibrinogen, vWF, fibrinonectin, and vitronectin and human platelet intergrin GP Ilb/IIIa plays an important role in thrombus formation. Using atomic force microscopy (AFM), we visualized the detailed structures of membrane and submembrane of the cell, and measured the interaction forces between a peptide modified cantilever probe tip and platelet surface from pN to nN levels under physiological buffer. Direct measurements of the debonding force for the RGD ligand - GP Ilb/IIIa system are presented. To eliminate the possible measurement of the hgand-receptor pair, or of the ligand and AFM tip, following desorption of the ligand; the cantilever tip surface was modified with covalent coupling chemistry rather than physical absorption. Our results showed that the single molecular rupturing force was 93.3 ± 10.41 pN with considerable chain extension in the receptor. The rupturing forces showed a logarithmic dependence of the rate of loading

scholarly journals Ultrastructural Studies of Platelet Aggregates From Human Subjects Receiving Clopidogrel and From a Patient With an Inherited Defect of an ADP-Dependent Pathway of Platelet Activation

1996 ◽  
Vol 16 (12) ◽  
pp. 1532-1543 ◽  
Author(s):  
Michel Humbert ◽  
Paquita Nurden ◽  
Claude Bihour ◽  
Jean-Max Pasquet ◽  
Joëlle Winckler ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Platelet Activation ◽  
Platelet Rich Plasma ◽  
Shape Change ◽  
High Dose ◽  
Platelet Response ◽  
Platelet Surface ◽  
Ultrastructural Studies ◽  
Contact Points ◽  
Platelet Aggregates

Our study investigated the effect of the antithrombotic drug clopidogrel (75 mg/d for 7 days) on the ultrastructure of platelet aggregates induced by ADP or 2-methylthio-ADP (2-MeS-ADP) in citrated platelet-rich plasma and examined the activation state of the GP IIb/IIIa complexes. Results were compared with those obtained for patient M.L., who has a congenital disorder characterized by a reduced and reversible platelet response to ADP. When untreated normal platelets were stimulated with high-dose ADP, electron microscopy revealed large and stable aggregates often surrounded by a layer of what appeared to be degranulated platelets. The reversible aggregates of platelets from subjects receiving clopidogrel or from patient M.L. did not show this layer. Electron microscopy showed that in both situations, the aggregates were composed of loosely bound platelets with few contact points. Immunogold labeling of ultrathin sections of Lowicryl-embedded aggregates formed by ADP or 2-MeS-ADP showed a much decreased platelet surface staining by (1) a polyclonal anti-fibrinogen antibody and (2) AP-6, a murine anti–ligand-induced binding site monoclonal antibody specific for GP IIb/IIIa complexes occupied with fibrinogen. Similar findings were seen after disaggregation, when many single platelets were present that showed no signs of secretion. Flow cytometry confirmed that the number of ligand-occupied GP IIb/IIIa complexes was much lower on platelets stimulated with ADP or 2-MeS-ADP after clopidogrel treatment. As expected from previous studies, ADP-induced platelet shape change and Ca 2+ influx were unaffected by clopidogrel. These results agree with the hypothesis that platelet activation by ADP is biphasic and highlight a receptor-induced activation pathway affected by clopidogrel (or congenitally impaired in patient M.L.) that is necessary for the full activation of GP IIb/IIIa and the formation of stable macroaggregates.

Sign in / Sign up

Export Citation Format

Share Document