Exosome poly-ubiquitin inhibits platelet activation, downregulates CD36 and inhibits pro-atherothombotic cellular functions. J Thromb Haemost 2014 Nov;12(11):1906-17
Date
08/29/2014Pubmed ID
25163645Pubmed Central ID
PMC4229405DOI
10.1111/jth.12712Scopus ID
2-s2.0-84916633753 (requires institutional sign-in at Scopus site) 97 CitationsAbstract
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 FeCl3 -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 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.
CONCLUSIONS: Platelet-derived exosomes inhibit athero-thrombotic processes by reducing CD36-dependent lipid loading of macrophages and by suppressing platelet thrombosis. Exosomes increase protein ubiquitination and enhance proteasome degradation of CD36.
Author List
Srikanthan S, Li W, Silverstein RL, McIntyre TMAuthor
Roy L. Silverstein MD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBlood Platelets
CD36 Antigens
Carotid Artery Diseases
Cell-Derived Microparticles
Chlorides
Cholesterol
Collagen
Disease Models, Animal
Exosomes
Ferric Compounds
Foam Cells
Humans
Lipoproteins, LDL
Mice, Inbred C57BL
Platelet Activation
Platelet Adhesiveness
Platelet Aggregation
Platelet Transfusion
Polyubiquitin
Proteasome Endopeptidase Complex
Proteolysis
Signal Transduction
Thrombocytopenia
Thrombosis
Time Factors
Ubiquitination
