INTRODUCTION: 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.
INTRODUCTION: 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-deficientmice 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: Gong-Qing Shen; Lin Li; Domenico Girelli; Sara B Seidelmann; Shaoqi Rao; Chun Fan; Jeong Euy Park; Quansheng Xi; Jing Li; Ying Hu; Oliviero Olivieri; Kandice Marchant; John Barnard; Roberto Corrocher; Robert Elston; June Cassano; Susan Henderson; Stanley L Hazen; Edward F Plow; Eric J Topol; Qing K Wang Journal: Am J Hum Genet Date: 2007-08-31 Impact factor: 11.025
Authors: Kieran L Quinn; Melanie Henriques; Arata Tabuchi; Bing Han; Hong Yang; Wei-Erh Cheng; Soumitra Tole; Hanpo Yu; Alice Luo; Emmanuel Charbonney; Elizabeth Tullis; Alan Lazarus; Lisa A Robinson; Heyu Ni; Blake R Peterson; Wolfgang M Kuebler; Arthur S Slutsky; Haibo Zhang Journal: Arterioscler Thromb Vasc Biol Date: 2011-08-04 Impact factor: 8.311
Authors: James L Daniel; Carol A Dangelmaier; Sripal Mada; Lorena Buitrago; Jianguo Jin; Wallace Y Langdon; Alexander Y Tsygankov; Satya P Kunapuli; Archana Sanjay Journal: J Biol Chem Date: 2010-04-16 Impact factor: 5.157