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Platelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype

Abstract

Dyslipidemia is associated with a prothrombotic phenotype; however, the mechanisms responsible for enhanced platelet reactivity remain unclear. Proatherosclerotic lipid abnormalities are associated with both enhanced oxidant stress and the generation of biologically active oxidized lipids, including potential ligands for the scavenger receptor CD36, a major platelet glycoprotein. Using multiple mouse in vivo thrombosis models, we now demonstrate that genetic deletion of Cd36 protects mice from hyperlipidemia-associated enhanced platelet reactivity and the accompanying prothrombotic phenotype. Structurally defined oxidized choline glycerophospholipids that serve as high-affinity ligands for CD36 were at markedly increased levels in the plasma of hyperlipidemic mice and in the plasma of humans with low HDL levels, were able to bind platelets via CD36 and, at pathophysiological levels, promoted platelet activation via CD36. Thus, interactions of platelet CD36 with specific endogenous oxidized lipids play a crucial role in the well-known clinical associations between dyslipidemia, oxidant stress and a prothrombotic phenotype.

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Figure 1: CD36 plays a role in thrombosis in vivo in the setting of hypercholesterolemia.
Figure 2: CD36 deficiency blunts platelet responses to agonists in hypercholesterolemic plasma.
Figure 3: Platelet CD36 specifically binds oxPCCD36 and LDL oxidized by MPO-H2O2-NO2 system.
Figure 4: oxPCCD36 activates platelet fibrinogen receptor integrin αIIbβ3 in a CD36-dependent manner.
Figure 5: oxPCCD36 induce platelet P-selectin expression in a CD36-dependent manner.

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Acknowledgements

We thank E. Plow for thoughtful comments and criticisms and W. Feng, W. Li and V. Verbovetskaya for technical assistance. This work was supported in part by National Institutes of Health grants HL077213 and HL053315 (E.A.P.) and by a Scientist Development Grant from the American Heart Association (E.A.P.), HL70621 and HL076491 (S.L.H.), HL 70083 (M.F.), HL072942 and HL46403 (R.L.S. and M.F.), HL071625, HL073311 and HL077107 (T.V.B.), HL53315 (R.G.S.), Cleveland Clinic Specialized Centers for Clinically Oriented Research (P01 HL077107, S.L.H.; and P50 HL81011, R.L.S. and M.F.) and the Cleveland Clinic Foundation General Clinical Research Center (M01 RR018390).

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Correspondence to Eugene A Podrez.

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Podrez, E., Byzova, T., Febbraio, M. et al. Platelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype. Nat Med 13, 1086–1095 (2007). https://doi.org/10.1038/nm1626

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