Role of Extracellular MicroRNAs in Atherosclerosis

Abstract

Atherosclerosis is a maladaptive inflammatory disease driven by the interplay between excess cholesterol accumulation in the arterial wall and the immune system. Macrophages are fundamental to the propagation of atherosclerosis due to their capacity to engulf modified lipoproteins and induce a pro‐inflammatory state. Macrophages can secrete miRNAs in exosomes as a form of intercellular communication during inflammation and infection. miRNAs are small noncoding RNAs that post‐transcriptionally regulate gene expression. Herein, we hypothesize that atherogenic macrophages secrete miRNAs in exosomes to mediate cell‐cell communication, which regulates the atherogenic response. To test this hypothesis, we first examined the miRNA expression profile of exosomes from control and atherogenic macrophages. Among the 88 differentially expressed miRNAs, 68 were down‐regulated whereas 20 were up‐regulated in exosomes from cholesterol‐loaded macrophages as compared with the control. qPCR confirmed the enrichment of several miRNAs such as miR‐146a, miR‐128, miR‐185, and miR‐503 in exosomes derived from atherogenic macrophages, whereas miR‐150 was downregulated in these exosomes. Bioinformatic pathway analysis suggests that atherogenic exosomal miRNAs may regulate cell migration and adhesion pathways via targeting the 3′UTR of migration/adhesion genes (i.e. integrin α3, VE‐cadherin, CXCR4). Interestingly, live cell imaging showed that exosomes secreted from cholesterol‐loaded macrophages were internalized by naïve macrophages and exogenous C. elegans miR‐39 could transfer from atherogenic macrophages to naïve cells. Thus, miRNAs secreted from atherogenic macrophages may promote atherosclerosis by regulating macrophage migration in the vessel wall and the role of these exo‐miRNAs will be tested in vitro and in vivo.