Knockdown of mesenchymal stem cell-derived exosomal LOC100129516 suppresses the symptoms of atherosclerosis via upregulation of the PPARγ/LXRα/ABCA1 signaling pathway

Mesenchymal stem cell (MSC) therapy has potential applications in treating atherosclerosis and coronary heart disease (CAD). Previous studies have demonstrated that MSCs are the most preferable sources of therapeutic exosomes, which carry long non-coding RNAs and participate in the progression of atherosclerosis. The results of our previous bioinformatics study demonstrated that the levels of LOC100129516 were significantly upregulated in peripheral blood mononuclear cells obtained from patients with CAD. However, the biological role of LOC100129516 in the development of atherosclerosis remains to be elucidated. In the present study, THP-1 cells were treated with oxidized low-density lipoproteins to induce foam cell formation in vitro. Reverse transcription-quantitative PCR (RT-qPCR) was performed to detect the levels of LOC100129516 in THP-1 macrophage-derived foam cells. In addition, an in vivomodel of atherosclerosis was established using Apolipoprotein E (ApoE) knockout (ApoE(−/−)) mice. The results of the RT-qPCR assays demonstrated that the levels of LOC100129516 were upregulated in THP-1 macrophage-derived foam cells. MSC-derived exosomes were able to deliver small interfering (si)-LOC100129516 to THP-1 cells to reduce the levels of LOC100129516. Moreover, transfection of si-LOC100129516 via exosomal delivery significantly decreased the levels of total cholesterol (TC), free cholesterol and cholesterol ester in THP-1 macrophage-derived foam cells. Exosomal-mediated delivery of si-LOC100129516 decreased TC levels and low-density lipoprotein levels in the ApoE(−/−) atherosclerosis mouse model. Mechanistically, exosomal-mediated delivery of si-LOC100129516 promoted cholesterol efflux by activating the peroxisome proliferator-activated receptor γ (PPARγ)/liver X receptor α (LXRα)/phospholipid-transporting ATPase ABCA1 (ABCA1) signaling pathway in vitro and in vivo. Collectively, these results suggested that exosomal-mediated delivery of si-LOC100129516, in which the exosomes were derived from MSCs, promoted cholesterol efflux and suppressed intracellular lipid accumulation, ultimately alleviating the progression of atherosclerosis via stimulation of the PPARγ/LXRα/ABCA1 signaling pathway.