Vav guanine nucleotide exchange factors link hyperlipidemia and a prothrombotic state

K Chen, W Li, J Major, SO Rahaman… - Blood, The Journal …, 2011 - ashpublications.org
K Chen, W Li, J Major, SO Rahaman, M Febbraio, RL Silverstein
Blood, The Journal of the American Society of Hematology, 2011ashpublications.org
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 …
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.
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