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

Abstract

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 vivo model 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.

Macrophage Gpx4 deficiency aggravates foam cell formation by regulating the expression of scavenger receptors, ABCA1, and ABCG1

“…The roles of ABCA1 and ABCG1, primary cholesterol efflux mediators, in limiting macrophage foam cell formation and atherogenesis have also been widely validated (Yvan‐Charvet et al, 2007). Previous studies showed that PPARγ/LXRα/ABCA1 axis mediates cholesterol efflux from macrophages and decreases foam cell formation (Jiang et al, 2017; Sun et al, 2021; Zheng et al, 2021). Chen et al demonstrated that Netrin‐1 inhibits ferroptosis by activating PPARγ/Nrf2/GPX4 signaling pathway in HT22 cells (Chen, 2023).…”

Therapeutic potential of exosome‐based personalized delivery platform in chronic inflammatory diseases

“…More importantly, the therapeutic research on cargo delivery strategies based on MSC-derived exosomes is becoming more and more extensive. The exogenous small interfering LOC100129516 was successfully delivered to THP-1 cells via MSC-derived exosomes, resulting in significantly lower levels of total cholesterol, free cholesterol, and cholesteryl ester in THP-1 macrophage-derived foam cells [98] . Finally, the progression of the disease was inhibited by modulating PPARγ/LXRα/ABCA1 signaling.…”

Mesenchymal Stem Cell-Derived Long Noncoding RNAs in Cardiac Injury and Repair

“…LncRNA LOC100129516 levels were found to be upregulated in macrophage-derived foam cells induced by oxidized low-density lipoproteins [ 74 ]. In an ApoE-/- atherosclerosis mouse model, exosomal delivery of small interfering RNA against LOC100129516 decreased total cholesterol and low-density lipoprotein levels through activation of the peroxisome proliferator-activated receptor γ (PPARγ)/liver X receptor α (LXRα)/phospholipid-transporting ATPase ABCA1 (ABCA1) signaling pathway, promoting cholesterol efflux and suppressing intracellular lipid accumulation [ 74 ].…”