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Mechanistic and Therapeutic Insights of Macrophage MicroRNA in Atherosclerosis

Macrophages are central players during atherosclerosis. Especially, macrophage cholesterol
efflux, which promote the removal of free cholesterol from foam cells, are crucial to prevent
lipid accumulation and reverse atherogenesis. microRNAs (miRNAs) are important regulators
of various pathways involved in atherosclerosis. During inflammation, macrophages secrete
extracellular vesicles (EVs) carrying miRNAs to communicate signals to nearby cells.
However, the role of macrophage-derived EVs in atherogenesis is not known. In the first study,
we find that EVs derived from cholesterol-loaded macrophages can inhibit macrophage
migration in vitro and in vivo. This effect appears to be mediated by the transfer of several
miRNAs, including miR-146a, to recipient macrophages where they repress the expression of
specific pro-migratory target genes Igf2bp1 and HuR. Our studies suggest that EV-derived
miRNAs secreted from atherogenic macrophages may accelerate the development of
atherosclerosis by decreasing cell migration and promoting macrophage entrapment in the
vessel wall. Understanding macrophage communication via EVs provided the rationale for the
design of nanoparticles (NPs) that mimic macrophage EVs to deliver beneficial miRNAs to
the atherosclerotic plaque. While cationic lipid/polymer-based NPs have been employed as
systemic delivery vehicles of siRNA, none of these have been used to deliver miRNAs to
macrophages in vivo. In the second study, we developed a chitosan NP platform for effective
delivery of miRNAs to alter macrophage function in vivo. We showed that our NPs made using
a cross-linked chitosan polymer can protect as well as transfer miR-33 to naïve macrophages
and regulate the expression of its target gene (Abca1) as well as cholesterol efflux in vitro and
in vivo. Finally, almost all miRNAs that have been characterized are efflux-repressing miRNA,
thereby accelerating atherosclerosis. miR-223 is one of a few miRNAs whose overexpression
can promote cholesterol efflux, modulate the inflammatory response, and thus, be antiatherogenic. However, its contribution to the pathogenesis of atherosclerosis in vivo and the
mechanism underlying its effects has not been thoroughly characterized. We herein find that
miR-223 is capable of suppressing plaque development via modulating cholesterol efflux and
inflammatory responses, thus may serve as a potential therapeutic to reduce atherosclerosis.
These effects of miR-223 appear to be dependent on the inhibition of its target gene, the
transcription factor Sp3. Overall, this thesis highlights the importance of both endogenous and
extracellular miRNAs in controlling different aspects of atherogenic response.

Identiferoai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/39691
Date02 October 2019
CreatorsNguyen, My-Anh
ContributorsRayner, Katey Jane
PublisherUniversité d'Ottawa / University of Ottawa
Source SetsUniversité d’Ottawa
LanguageEnglish
Detected LanguageEnglish
TypeThesis
Formatapplication/pdf

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