Mechanisms of Action of MiRNAs and LncRNAs in Extracellular Vesicle in Atherosclerosis

Abstract

Atherosclerosis, a complex chronic inflammatory disease, involves multiple alterations of diverse cells, including endothelial cells (ECs), vascular smooth muscle cells (VSMCs), monocytes, macrophages, dendritic cells (DCs), platelets, and even mesenchymal stem cells (MSCs). Globally, it is a common cause of morbidity as well as mortality. It leads to myocardial infarctions, stroke and disabling peripheral artery disease. Extracellular vesicles (EVs) are a heterogeneous group of cell-derived membranous structures that secreted by multiple cell types and play a central role in cell-to-cell communication by delivering various bioactive cargos, especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Emerging evidence demonstrated that miRNAs and lncRNAs in EVs are tightly associated with the initiation and development of atherosclerosis. In this review, we will outline and compile the cumulative roles of miRNAs and lncRNAs encapsulated in EVs derived from diverse cells in the progression of atherosclerosis. We also discuss intercellular communications via EVs. In addition, we focused on clinical applications and evaluation of miRNAs and lncRNAs in EVs as potential diagnostic biomarkers and therapeutic targets for atherosclerosis.

Keywords: atherosclerosis; endothelial cells; extracellular vesicles; long non-coding RNA; microRNA; vascular smooth muscle cells.

Figure 1

Hallmarks of EVs. EVs can be secreted by almost all cells. EVs carry various molecular cargos, including proteins, lipids, metabolites, and nucleic acids (mRNAs, miRNAs, lncRNAs, etc.). Proteins include tetraspanins (CD9, CD63, CD81, and CD82), ESCRT proteins (such as ALIX and TSG101), and syntenin-1 have emerged as commonly used markers for EVs. Some molecules are carried on the surface of EVs, including major histocompatibility complex (MHC) class I/II molecules, flotillin, and transmembrane proteins, etc.

Figure 2

MiRNAs and lncRNAs in EVs mediate intercellular communication in atherosclerosis. EVs, secreted by different cells, including ECs, VSMCs, and immune cells, are implicated in atherosclerosis via transferring miRNAs and lncRNAs. KLF2-expressing ECs-derived EVs reduced atherosclerotic lesion formation in ApoE (-/-) mice via delivering miR-143/145. Ox-LDL-induced ECs secret EVs regulate VSMCs proliferation and migration through the delivery of RNCR3. On the contrary, XBP1 splicing in VSMCs can control ECs migration via EVs inclusion of miRNA-150 and miRNA-150-driven VEGF-A/VEGFR/PI3K/Akt pathway. MiR-221/222 in VSMCs-derived EVs repressed HUVECs autophagy via PTEN/Akt pathway. MiR-155 was elevated in KLF5-overexpressing VSMCs-derived EVs and enhanced atherosclerosis development via inhibiting ECs proliferation, migration, and re-endothelialization. ECs-derived EVs carrying miRNA-126, miRNA-210, miRNA-216, and MALAT1 alleviate macrophages polarization and infiltration. The transfer of miRNA-126-3P to macrophages can reduce atherosclerotic plaque area via EVs. Overexpression of miR-155 in EVs from ox-LDL-induced macrophages regulated ECs inflammation by modulating Sirt1/AMPKα2/eNOS and RAC1/PAK2 pathways. GAS5 was upregulated in THP-1 cells-derived EVs after oxLDL stimulation. GAS5 was involved in regulating ECs apoptosis and stimulating atherosclerosis. MiRNA-92a and miRNA-195 were increased in EVs from VSMCs and they could regulate inflammatory reaction through enhancing the expression of IL-6 and CXCL1 in macrophages. MiR-21-3p in EVs from nicotine-treated macrophages accelerate atherosclerosis by PTEN-mediated VSMC migration and proliferation. MiR-106a-3p was increased in EVs from ox-LDL stimulated THP-1 and it could promote cell proliferation of VSMCs. DCs-derived EVs transferred miRNA-146a into HUVECs to protect HUVECs from a second stimulation of TNF-α. Loss of MALAT1 in EVs from ox-LDL-induced VECs promoted DCs maturation in atherosclerosis development via Nrf2 pathway. MiR-25-3p was upregulated in thrombin-induced platelet-derived EVs and alleviated ox-LDL-induced ECs inflammation. Activated platelet-derived EVs promote ECs proliferation by transferring miRNA-126 and enhancing the production of VEGF, bFGF, and TGF-β1. Thrombin stimulated platelet-derived EVs repressed the production of PDGFRβ in VSMCs via the delivery of miR-223, miR-339, and miR-21, promoting cell apoptosis. MiRNA-30 and miRNA-125a in EVs released from MSCs reduced the expression of DLL4 in ECs, mediating angiogenesis. MSCs-derived EVs promote the proliferation and migration of ECs through delivering miRNA-126-3P. Besides, the transfer of miR-125b from MSCs-derived EVs to VSMCs inhibited VSMC proliferation by inhibiting Myo1e.