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Deficiency of LRP8 in mice is associated with altered platelet function and prolonged time for in vivo thrombosis.

AbstractINTRODUCTION:
Our group has previously reported genetic studies associating polymorphisms in the low density lipoprotein receptor related protein 8 (LRP8) gene with myocardial infarction. The aim of this study was to define the role of platelet surface LRP8 in thrombosis.
MATERIALS AND METHODS:
Flow cytometry, aggregometry, intravital microscopy and tail bleeding assays were used to examine platelet function and hemostasis in LRP8-deficient mice and littermate controls.
RESULTS:
We demonstrated that activation of platelets from both LRP8(+/-) and LRP8(-/-) mice was reduced in vitro in response to either ADP or thrombin. In vivo, LRP8-hemizygous and LRP8(-/-) mice demonstrated 200% and 68% increased time for carotid occlusion in response to FeCl(3) injury, respectively. Moreover, lipidated apoE3, a ligand for LRP8, inhibited platelet activation in a dose-dependent fashion. This inhibition was markedly attenuated in LRP8(-/-) but not LRP8(+/-) mice and did not result from membrane cholesterol efflux or a nitric oxide dependent pathway. Tail bleeding times were unaffected in both genotypes.
CONCLUSIONS:
Our results suggest that LRP8 is capable of altering thrombosis without affecting normal hemostasis through mechanisms both dependent on and independent of apoE. This suggests a means whereby clot formation could be affected in humans with LRP8 gene variants.
AuthorsJason O Robertson, Wei Li, Roy L Silverstein, Eric J Topol, Jonathan D Smith
JournalThrombosis research (Thromb Res) Vol. 123 Issue 4 Pg. 644-52 (Feb 2009) ISSN: 0049-3848 [Print] United States
PMID18706682 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Apolipoprotein E3
  • Chlorides
  • Ferric Compounds
  • LDL-Receptor Related Proteins
  • Receptors, Lipoprotein
  • low density lipoprotein receptor-related protein 8
  • Nitric Oxide
  • ferric chloride
Topics
  • Animals
  • Apolipoprotein E3 (pharmacology)
  • Blood Platelets (drug effects, physiology)
  • Chlorides
  • Ferric Compounds
  • Humans
  • LDL-Receptor Related Proteins
  • Mice
  • Mice, Knockout
  • Nitric Oxide (pharmacology)
  • Platelet Activation (drug effects)
  • Receptors, Lipoprotein (deficiency)
  • Thrombosis (chemically induced, physiopathology)

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