Vav guanine nucleotide exchange factors link hyperlipidemia and a prothrombotic state. Blood 2011 May 26;117(21):5744-50
Date
03/24/2011Pubmed ID
21427288Pubmed Central ID
PMC3110031DOI
10.1182/blood-2009-01-201970Scopus ID
2-s2.0-79957586599 (requires institutional sign-in at Scopus site) 56 CitationsAbstract
Platelet hyperactivity associated with hyperlipidemia contributes to development of a pro-thrombotic state. We previously showed that oxidized LDL (oxLDL) formed in the setting of hyperlipidemia and atherosclerosis initiated a CD36-mediated signaling cascade leading to platelet hyperactivity. We now show that the guanine nucleotide exchange factors Vav1 and Vav3 were tyrosine phosphorylated in platelets exposed to oxLDL. Pharmacologic inhibition of src family kinases abolished Vav1 phosphorylation by oxLDL in vitro. Coimmunoprecipitations revealed the tyrosine phosphorylated form of src kinase Fyn was associated with Vav1 in platelets exposed to oxLDL. Using a platelet aggregation assay, we demonstrated that Vav1 deficiency, Fyn deficiency, or Vav1/Vav3 deficiency protected mice from diet-induced platelet hyperactivity. Furthermore, flow cytometric analysis revealed that Vav1/Vav3 deficiency significantly inhibited oxLDL-mediated integrin αIIbβIII activation of platelets costimulated with ADP. Finally, we showed with an in vivo carotid artery thrombosis model that genetic deletion of Vav1 and Vav3 together may prevent the development of occlusive thrombi in mice fed a high-fat diet. These findings implicate Vav proteins in oxLDL-mediated platelet activation and suggest that Vav family member(s) may act as critical modulators linking a prothrombotic state and hyperlipidemia.
Author List
Chen K, Li W, Major J, Rahaman SO, Febbraio M, Silverstein RLAuthor
Roy L. Silverstein MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBlood Platelets
Blotting, Western
Carotid Artery Thrombosis
Dietary Fats
Female
Flow Cytometry
Fluorescent Antibody Technique
Humans
Hyperlipidemias
Immunoprecipitation
Lipoproteins, LDL
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Phosphorylation
Platelet Activation
Platelet Aggregation
Proto-Oncogene Proteins c-fyn
Proto-Oncogene Proteins c-vav
Signal Transduction
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Thrombosis
Tyrosine
src-Family Kinases
