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Exosome poly‐ubiquitin inhibits platelet activation, downregulates CD 36 and inhibits pro‐atherothombotic cellular functions
Author(s) -
Srikanthan S.,
Li W.,
Silverstein R. L.,
McIntyre T. M.
Publication year - 2014
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12712
Subject(s) - cd36 , exosome , microbiology and biotechnology , platelet activation , chemistry , ubiquitin , microvesicles , platelet , biology , immunology , biochemistry , microrna , receptor , gene
Summary Introduction Activated platelets shed microparticles from plasma membranes, but also release smaller exosomes from internal compartments. While microparticles participate in athero‐thrombosis, little is known of exosomes in this process. Materials & Methods Ex vivo biochemical experiments with human platelets and exosomes, and FeCl 3 ‐induced murine carotid artery thrombosis. Results 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 FeCl 3 ‐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. CD 36 promotes platelet activation, and exosomes dramatically reduced platelet CD 36. CD 36 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 CD 36 ligands, but instead sharply reduced total macrophage CD 36 content. Exosomal proteins, in contrast to microparticle or cellular proteins, were highly adducted by ubiquitin. Exosomes enhanced ubiquitination of cellular proteins, including CD 36, and blockade of proteosome proteolysis with MG ‐132 rescued CD 36 expression. Recombinant unanchored K 48 poly‐ubiquitin behaved similarly to exosomes, inhibiting platelet function, macrophage CD 36 expression and macrophage particle uptake. Conclusions Platelet‐derived exosomes inhibit athero‐thrombotic processes by reducing CD 36‐dependent lipid loading of macrophages and by suppressing platelet thrombosis. Exosomes increase protein ubiquitination and enhance proteasome degradation of CD 36.