title: Vav guanine nucleotide exchange factors link hyperlipidemia and a prothrombotic state.
abstract: 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.
authors.affiliation: Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Kan
authors.initials: K
authors.lastname: Chen
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Jennifer
authors.initials: J
authors.lastname: Major
authors.forename: Shaik Ohidar
authors.initials: SO
authors.lastname: Rahaman
authors.forename: Maria
authors.initials: M
authors.lastname: Febbraio
authors.forename: Roy L
authors.initials: RL
authors.lastname: Silverstein
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D015153:Blotting, Western; D002341:Carotid Artery Thrombosis / Q000378:metabolism; D004041:Dietary Fats; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D006949:Hyperlipidemias / Q000378:metabolism* / Q000473:pathology; D047468:Immunoprecipitation; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D015539:Platelet Activation; D010974:Platelet Aggregation; D051076:Proto-Oncogene Proteins c-fyn / Q000502:physiology*; D051567:Proto-Oncogene Proteins c-vav / Q000502:physiology*; D015398:Signal Transduction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013927:Thrombosis / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control; D014443:Tyrosine / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D008077:Lipoproteins, LDL; D051567:Proto-Oncogene Proteins c-vav; C496619:Vav1 protein, mouse; C496622:Vav3 protein, mouse; C099252:oxidized low density lipoprotein; D014443:Tyrosine; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D019061:src-Family Kinases