Abstract | INTRODUCTION: 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.
|
Authors | Jason O Robertson, Wei Li, Roy L Silverstein, Eric J Topol, Jonathan D Smith |
Journal | Thrombosis research
(Thromb Res)
Vol. 123
Issue 4
Pg. 644-52
(Feb 2009)
ISSN: 0049-3848 [Print] United States |
PMID | 18706682
(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)
|