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ROLE OF EXOSOMES IN ATHEROTHROMBOTIC PROCESSES

Srikanthan, Sowmya
http://rave.ohiolink.edu/etdc/view?acc_num=case1417774233

Abstract Details

2014, Doctor of Philosophy, Case Western Reserve University, Molecular Medicine.
Atherothrombosis is characterized by the disruption of atherosclerotic plaque with a superimposed thrombus formation and is a major contributor to cardiovascular mortality and morbidity. Compelling evidence support the hypothesis that platelets, macrophages, and circulating microparticles play a critical role in the pathology of this disease. Activated platelets shed microparticles derived from the plasma membrane and exosomes from multi-vesiculated endosomes. While microparticles promote athero-thrombosis, little is known of the potential participation of exosomes in this process. I found both microparticles and exosomes are abundant in human plasma. I observed that platelet-derived exosomes selectively suppressed collagen-stimulated platelet aggregation and reduced adhesion to collagen-coated microfluidic channels at high shear. In contrast, microparticles promoted adhesion. Considering these observations, I hypothesized that exosomes and microparticles play opposite roles in regulating thrombus formation. To test this hypothesis, I performed an in vivo thrombosis assay using the FeCl3-induced carotid artery injury model in mice. Injected exosomes inhibited occlusive thrombosis in FeCl3-damaged murine carotid arteries. To demonstrate that platelets were the specific targets, I purified platelets and exposed them to exosomes ex vivo prior to transfusion into irradiated, thrombocytopenic mice. I found that exosomes inhibited occlusive thrombosis in carotid arteries. CD36 promotes platelet activation, and interestingly, total cellular CD36 protein expression in platelets and macrophages was dramatically reduced by exosomes. CD36 is also expressed by macrophages where it binds and internalizes oxidized LDL and microparticles, supplying intracellular lipid to form foam cells. Platelet exosomes inhibited macrophage No2LDL binding, internalization, and cholesterol loading. Exosomes were not CD36 ligands, but instead reduced platelet and macrophage CD36 surface expression. I also found exosomal proteins were decorated with ubiquitin, and exosomes enhanced ubiquitination of macrophage CD36. CD36 ubiquitination was increased by blockade of proteosome activity with MG-132, which rescued CD36 expression. Recombinant unanchored K48 poly-ubiquitin behaved similarly to exosomes and reduced macrophage CD36 expression and microparticle uptake. This ubiquitin polymer also suppressed collagen-stimulated platelet aggregation. In conclusion, my findings suggest that platelet-derived exosomes inhibit athero-thrombosis by reducing CD36-dependent lipid loading of macrophages through enhancement of proteasome degradation of CD36, and by suppressing platelet thrombosis through the poly-ubiquitin they contain.
Thomas McIntyre (Advisor)
105 p.
Biology; Cellular Biology; Molecular Biology

Recommended Citations

Citations

  • Srikanthan, S. (2014). ROLE OF EXOSOMES IN ATHEROTHROMBOTIC PROCESSES [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1417774233

    APA Style (7th edition)

  • Srikanthan, Sowmya. ROLE OF EXOSOMES IN ATHEROTHROMBOTIC PROCESSES. 2014. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1417774233.

    MLA Style (8th edition)

  • Srikanthan, Sowmya. "ROLE OF EXOSOMES IN ATHEROTHROMBOTIC PROCESSES." Doctoral dissertation, Case Western Reserve University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1417774233

    Chicago Manual of Style (17th edition)

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© 2014, some rights reserved.Creative Commons License ROLE OF EXOSOMES IN ATHEROTHROMBOTIC PROCESSES by Sowmya Srikanthan is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.