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MicroRNA-19b-3p-containing extracellular vesicles derived from macrophages promote the development of atherosclerosis by targeting JAZF1.

ABSTRACT: Atherosclerosis has been regarded as a major contributor to cardiovascular disease. The role of extracellular vesicles (EVs) in the treatment of atherosclerosis has been increasingly reported. In this study, we set out to investigate the effect of macrophages-derived EVs (M-EVs) containing miR-19b-3p in the progression of atherosclerosis, with the involvement of JAZF1. Following isolation of EVs from macrophages, the M-EVs were induced with ox-low density lipoprotein (LDL) (ox-LDL-M-EVs), and co-cultured with vascular smooth muscle cells (VSMCs). RT-qPCR and western blot assay were performed to determine the expression of miR-19b-3p and JAZF1 in M-EVs and in VSMCs. Lentiviral infection was used to overexpress or knock down miR-19b-3p. EdU staining and scratch test were conducted to examine VSMC proliferation and migration. Dual-luciferase gene reporter assay was performed to examine the relationship between miR-19b-3p and JAZF1. In order to explore the role of ox-LDL-M-EVs carrying miR-19b-3p in atherosclerotic lesions in vivo, a mouse model of atherosclerosis was established through high-fat diet induction. M-EVs were internalized by VSMCs. VSMC migration and proliferation were promoted by ox-LDL-M-EVs. miR-19b-3p displayed upregulation in ox-LDL-M-EVs. miR-19b-3p was transferred by M-EVs into VSMCs, thereby promoting VSMC migration and proliferation. mir-19b-3p targeted JAZF1 to decrease its expression in VSMCs. Atherosclerosis lesions were aggravated by ox-LDL-M-EVs carrying miR-19b-3p in ApoE^-/- mice. Collectively, this study demonstrates that M-EVs containing miR-19b-3p accelerate migration and promotion of VSMCs through targeting JAZF1, which promotes the development of atherosclerosis.

SUBMITTER: Wang Q

PROVIDER: S-EPMC8742201 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Paracrine signaling between tumor and surrounding stromal cells is critical for the maintenance of tumor microenvironment during ovarian cancer progression. Small extracellular vesicles (sEVs; exosomes in particular) are nano-sized vesicles secreted actively by many cells including tumor cells and are found to have fundamental roles in intercellular communication through shuttling functional RNAs. Although microRNAs (also called miRNAs or miRs), small non-coding RNAs regulating gene expression, are selectively accumulated in tumor sEVs and can mediate intercellular communication, the exact biological mechanisms underlying the functions of exosomal miRNAs in ovarian tumor angiogenesis remain unclear. In this study, sEVs were isolated from conditioned medium of the human ovarian carcinoma cell line SKOV-3 using ExoQuick Exosome Precipitation Solution, and characterized by scanning electron microscopy, dynamic light scattering, and immunoblotting. To elucidate the possible paracrine effects on ovarian tumor cell-derived sEVs (TD-sEVs), we investigated the angiogenesis-related signaling events triggered by TD-sEVs in endothelial cells. Due to the possible role in ovarian tumor pathogenesis, we focused on miR-141-3p which was detected to be enriched in TD-sEVs compared with their corresponding donor cells. We identified that sEV transfer of miR-141-3p considerably reduced the expression levels of cytokine-inducible suppressors of cytokine signaling (SOCS)-5 leading to up-regulated JAK-STAT3 pathway in endothelial cells. We also observed that sEV-shuttled miR-141-3p may up-regulate the expression of VEGFR-2 in endothelial cells which leads to promoting endothelial cell migration and angiogenesis. The putative role of miR-141-3p shuttled by TD-sEVs in regulating VEGFR-2 expression was demonstrated by the ability of anti-miR-141-3p to rescue the promoting effects of TD-sEVs on the expression of VEGFR-2 in endothelial cells. Our results also revealed that TD-sEVs trigger the intracellular reactive oxygen species (ROS)-dependent activation of NF-?B signaling in endothelial cells. Taken together, our findings propose a novel model in which sEV transfer of epithelial ovarian cancer-secreted miR-141-3p plays as a significant mediator of intercellular communication, promoting endothelial cell angiogenesis.

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MicroRNA-19b-3p-containing extracellular vesicles derived from macrophages promote the development of atherosclerosis by targeting JAZF1.

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