Dataset Information

Identification of coagulation factor XI as a ligand for platelet apolipoprotein E receptor 2 (ApoER2).

ABSTRACT: Factor XI (FXI) promotes hemostasis and thrombosis through enhancement of thrombin generation and has been shown to play a critical role in the formation of occlusive thrombi in arterial injury models. The aim of this study was to investigate the mechanisms governing interactions between FXI and platelets.Platelet adhesion to immobilized FXI was abrogated in the presence of the low-density lipoprotein (LDL) receptor antagonist, receptor-associated protein (RAP), soluble recombinant apolipoprotein E receptor 2 (ApoER2), or the LDL-binding domain 1 or 2 of ApoER2. FXI supported wild-type murine platelet binding; in contrast, ApoER2-deficient murine platelets did not adhere to FXI. In the presence of shear, platelet aggregates formed on FXI or activated FXI (FXIa) surfaces, whereas the presence of RAP, binding domain 1 of ApoER2, or an anti-GPIb alpha mAb blocked platelet adhesion to FXI or FXIa under shear. Soluble FXI bound to immobilized ApoER2' with an affinity of 61 nmol/L.This study has identified apolipoprotein E receptor 2 (ApoER2, LRP8), a member of the LDL receptor family, as a platelet receptor for FXI. The interaction of FXI with other cell types that express ApoER2 remains to be explored.

SUBMITTER: White-Adams TC

PROVIDER: S-EPMC2756776 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Identification of coagulation factor XI as a ligand for platelet apolipoprotein E receptor 2 (ApoER2).

White-Adams Tara C TC Berny Michelle A MA Tucker Erik I EI Gertz Jacqueline M JM Gailani David D Urbanus Rolf T RT de Groot Philip G PG Gruber András A McCarty Owen J T OJ

Arteriosclerosis, thrombosis, and vascular biology 20090806 10

<h4>Objective</h4>Factor XI (FXI) promotes hemostasis and thrombosis through enhancement of thrombin generation and has been shown to play a critical role in the formation of occlusive thrombi in arterial injury models. The aim of this study was to investigate the mechanisms governing interactions between FXI and platelets.<h4>Methods and results</h4>Platelet adhesion to immobilized FXI was abrogated in the presence of the low-density lipoprotein (LDL) receptor antagonist, receptor-associated pr ...[more]

PMID: 19661487

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Project description:High levels of factor XI (FXI) increase the risk of thromboembolic disease. However, the genetic and environmental factors regulating FXI expression are still largely unknown. The aim of our study was to evaluate the regulation of FXI by microRNAs (miRNAs) in the human liver. In silico prediction yielded four miRNA candidates that might regulate FXI expression. HepG2 cells were transfected with miR-181a-5p, miR- 23a-3p, miR-16-5p and miR-195-5p. We used mir-494, which was not predicted to bind to F11, as a negative control. Only miR-181a-5p caused a significant decrease both in FXI protein and F11 mRNA levels. In addition, transfection with a miR-181a-5p inhibitor in PLC/PRF/5 hepatic cells increased both the levels of F11 mRNA and extracellular FXI. Luciferase assays in human colon cancer cells deficient for Dicer (HCT-DK) demonstrated a direct interaction between miR-181a-5p and 3'untranslated region of F11. Additionally, F11 mRNA levels were inversely and significantly correlated with miR-181a-5p levels in 114 healthy livers, but not with miR-494. This study demonstrates that FXI expression is directly regulated by a specific miRNA, miR-181a-5p, in the human liver. Future studies are necessary to further investigate the potential consequences of miRNA dysregulation in pathologies involving FXI. In the study presented here, we report arrays including 1,898 human mature miRNAs (LCSciences, Houston, TX; Sanger mirBase Release 18.0) using total RNA extracted from a healthy human liver sample E122; a Caucasian donor that gave informed consent were provided by biobanc CIBERehd. Human liver studies were apporved by Local Ethics Committee from Hospital Universitario Morales Meseguer in Murcia. In the study presented here, we report arrays including 2,019 human mature miRNAs (LCSciences, Houston, TX; Sanger mirBase Release 19.0) using total RNA extracted from 3 healthy human liver samples (662, 664, 771) from Caucasian donors that gave informed consent were provided by St. Jude Liver Resource at St. Distribution System and by cooperative Human Tissue Network. Human liver studies were apporved by Local Ethics Committee from Hospital Universitario Morales Meseguer in Murcia

Dataset Information

Identification of coagulation factor XI as a ligand for platelet apolipoprotein E receptor 2 (ApoER2).

Publications

Identification of coagulation factor XI as a ligand for platelet apolipoprotein E receptor 2 (ApoER2).

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