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Prothrombotic Platelet Signaling By the Scavenger Receptor CD36

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2009, Doctor of Philosophy, Case Western Reserve University, Cell Biology.
Platelet hyperactivity associated with hyperlipidemia may contribute to development of a pro-thrombotic state. We previously showed that oxidized LDL (oxLDL) formed in the setting of hyperlipidemia and atherosclerosis activated platelets in a CD36 dependent manner. We now show that MAP kinase JNK2 and its upstream activator MKK4 were phosphorylated in platelets exposed to oxLDL. Using apoe-/- mice as a model of hyperlipidemia we showed that JNK was constitutively phosphorylated in platelets in a CD36-dependent manner. Inhibition of src kinase activity reduced JNK phosphorylation by oxLDL. Immunoprecipitations revealed that active phosphorylated forms of src kinases Fyn and Lyn were recruited to CD36 in platelets exposed to oxLDL. We also showed that Vav, a guanine nucleotide exchange factor for Rho/Rac small GTPases was phosphorylated upon oxLDL treatment. Co-immunoprecipitation revealed Vav-associated Fyn was phosphorylated upon oxLDL treatment. Pharmacological inhibition of the MAP kinase JNK or src family kinases abolished platelet activation by oxLDL in vitro. Using a murine carotid artery thrombosis model we demonstrated CD36-dependent phosphorylation of platelet JNK within thrombi. Pharmacological inhibition of JNK prolonged thrombosis times in wild type but not cd36 null mice in vivo. In addition, in vitro functional studies demonstrated that western diet feeding increased platelet aggregation from WT mice and this phenotype was absent in vav-/- mice. These findings suggest that a specific CD36-dependent signaling pathway is required for platelet activation by oxLDL and may provide insights related to development of novel anti-platelet therapies more relevant to atherothrombosis than to normal hemostasis.
Thomas McIntyre, PhD (Committee Chair)
Roy Silverstein, MD (Advisor)
Gary Landreth, PhD (Committee Member)
Edward Plow (Committee Member)
126 p.

Recommended Citations

Citations

  • Chen, K. (2009). Prothrombotic Platelet Signaling By the Scavenger Receptor CD36 [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1226608419

    APA Style (7th edition)

  • Chen, Kan. Prothrombotic Platelet Signaling By the Scavenger Receptor CD36. 2009. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1226608419.

    MLA Style (8th edition)

  • Chen, Kan. "Prothrombotic Platelet Signaling By the Scavenger Receptor CD36." Doctoral dissertation, Case Western Reserve University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1226608419

    Chicago Manual of Style (17th edition)