Exosome poly‐ubiquitin inhibits platelet activation, downregulates CD 36 and inhibits pro‐atherothombotic cellular functions

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Both microparticles and exosomes were abundant in human plasma. Platelet‐derived exosomes suppressed ex vivo platelet aggregation and reduced adhesion to collagen‐coated microfluidic channels at high shear. Injected exosomes inhibited occlusive thrombosis in FeCl3‐damaged murine carotid arteries. Control platelets infused into irradiated, thrombocytopenic mice reconstituted thrombosis in damaged carotid arteries, but failed to do so after prior ex vivo incubation with exosomes.CD36 promotes platelet activation, and exosomes dramatically reduced platelet CD36.CD36 is also expressed by macrophages, where it binds and internalizes oxidized LDL and microparticles, supplying lipid to promote foam cell formation. Platelet exosomes inhibited oxidized‐LDL binding and cholesterol loading into macrophages. Exosomes were not competitive CD36 ligands, but instead sharply reduced total macrophage CD36 content. Exosomal proteins, in contrast to microparticle or cellular proteins, were highly adducted by ubiquitin. Exosomes enhanced ubiquitination of cellular proteins, including CD36, and blockade of proteosome proteolysis with MG‐132 rescued CD36 expression. Recombinant unanchored K48 poly‐ubiquitin behaved similarly to exosomes, inhibiting platelet function, macrophage CD36 expression and macrophage particle uptake.


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