Knockdown of mesenchymal stem cell‑derived exosomal LOC100129516 suppresses the symptoms of atherosclerosis via upregulation of the PPARγ/LXRα/ABCA1 signaling pathway Corrigendum in /10.3892/ijmm.2022.5106

Sun,Limin; He,Xin; Zhang,Tao; Han,Yaling; Tao,Guizhou

doi:10.3892/ijmm.2021.5041

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

Corrigendum in: /10.3892/ijmm.2022.5106

Authors:
- Limin Sun
- Xin He
- Tao Zhang
- Yaling Han
- Guizhou Tao
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Affiliations: Department of Medicine, Soochow University, Suzhou, Jiangsu 215123, P.R. China, Department of Cardiology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China, Department of General Practice, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China, Department of Cardiology, General Hospital of Northern Theater Command, Shenyang, Liaoning 110016, P.R. China
Published online on: October 4, 2021 https://doi.org/10.3892/ijmm.2021.5041
Article Number: 208
Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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1	Falk E: Pathogenesis of atherosclerosis. J Am Coll Cardiol. 47:C7–C12. 2006. View Article : Google Scholar : PubMed/NCBI
2	Tedgui A and Mallat Z: Cytokines in atherosclerosis: Pathogenic and regulatory pathways. Physiol Rev. 86:515–581. 2006. View Article : Google Scholar : PubMed/NCBI
3	Weber C and Noels H: Atherosclerosis: Current pathogenesis and therapeutic options. Nat Med. 17:1410–1422. 2011. View Article : Google Scholar
4	Lechner K, von Schacky C, McKenzie AL, Worm N, Nixdorff U, Lechner B, Kränkel N, Halle M, Krauss RM and Scherr J: Lifestyle factors and high-risk atherosclerosis: Pathways and mechanisms beyond traditional risk factors. Eur J Prev Cardiol. 27:394–406. 2020. View Article : Google Scholar :
5	Shoeibi S: Diagnostic and theranostic microRNAs in the pathogenesis of atherosclerosis. Acta Physiol (Oxf). 228:e133532020. View Article : Google Scholar
6	Kunitomo M: Oxidative stress and atherosclerosis. Yakugaku Zasshi. 127:1997–2014. 2007.In Japanese. View Article : Google Scholar : PubMed/NCBI
7	Li TT, Wang ZB, Li Y, Cao F, Yang BY and Kuang HX: The mechanisms of traditional Chinese medicine underlying the prevention and treatment of atherosclerosis. Chin J Nat Med. 17:401–412. 2019.PubMed/NCBI
8	Zarzycka B, Nicolaes GA and Lutgens E: Targeting the adaptive immune system: New strategies in the treatment of atherosclerosis. Expert Rev Clin Pharmacol. 8:297–313. 2015. View Article : Google Scholar : PubMed/NCBI
9	Wang C, Niimi M, Watanabe T, Wang Y, Liang J and Fan J: Treatment of atherosclerosis by traditional Chinese medicine: Questions and quandaries. Atherosclerosis. 277:136–144. 2018. View Article : Google Scholar
10	Vaidyanathan K and Gopalakrishnan S: Nanomedicine in the diagnosis and treatment of atherosclerosis - a systematic review. Cardiovasc Hematol Disord Drug Targets. 17:119–131. 2017. View Article : Google Scholar
11	Fasolo F, Di Gregoli K, Maegdefessel L and Johnson JL: Non-coding RNAs in cardiovascular cell biology and atherosclerosis. Cardiovasc Res. 115:1732–1756. 2019. View Article : Google Scholar : PubMed/NCBI
12	Varol C, Mildner A and Jung S: Macrophages: Development and tissue specialization. Annu Rev Immunol. 33:643–675. 2015. View Article : Google Scholar : PubMed/NCBI
13	Smigiel KS and Parks WC: Macrophages, wound healing, and fibrosis: Recent insights. Curr Rheumatol Rep. 20:172018. View Article : Google Scholar : PubMed/NCBI
14	Kuznetsova T, Prange KHM, Glass CK and de Winther MPJ: Transcriptional and epigenetic regulation of macrophages in atherosclerosis. Nat Rev Cardiol. 17:216–228. 2020. View Article : Google Scholar :
15	Moore KJ and Tabas I: Macrophages in the pathogenesis of atherosclerosis. Cell. 145:341–355. 2011. View Article : Google Scholar :
16	Barrett TJ: Macrophages in atherosclerosis regression. Arterioscler Thromb Vasc Biol. 40:20–33. 2020. View Article : Google Scholar
17	Uccelli A, Moretta L and Pistoia V: Mesenchymal stem cells in health and disease. Nat Rev Immunol. 8:726–736. 2008. View Article : Google Scholar
18	Li J, Xue H, Li T, Chu X, Xin D, Xiong Y, Qiu W, Gao X, Qian M, Xu J, et al: Exosomes derived from mesenchymal stem cells attenuate the progression of atherosclerosis in ApoE^−/− mice via miR-let7 mediated infiltration and polarization of M2 macrophage. Biochem Biophys Res Commun. 510:565–572. 2019. View Article : Google Scholar : PubMed/NCBI
19	Kalluri R and LeBleu VS: The biology, function, and biomedical applications of exosomes. Science. 367:eaau69772020. View Article : Google Scholar :
20	Sasaki R, Kanda T, Yokosuka O, Kato N, Matsuoka S and Moriyama M: Exosomes and hepatocellular carcinoma: From BENCH TO BEDside. Int J Mol Sci. 20:14062019. View Article : Google Scholar
21	Huang P, Wang L, Li Q, Tian X, Xu J, Xu J, Xiong Y, Chen G, Qian H, Jin C, et al: Atorvastatin enhances the therapeutic efficacy of mesenchymal stem cells-derived exosomes in acute myocardial infarction via up-regulating long non-coding RNA H19. Cardiovasc Res. 116:353–367. 2020. View Article : Google Scholar
22	Yue Y, Li YQ, Fu S, Wu YT, Zhu L, Hua L, Lv JY, Li YL and Yang DL: Osthole inhibits cell proliferation by regulating the TGF-β1/Smad/p38 signaling pathways in pulmonary arterial smooth muscle cells. Biomed Pharmacother. 121:1096402020. View Article : Google Scholar
23	Charles Richard JL and Eichhorn PJA: Platforms for investigating lncRNA functions. SLAS Technol. 23:493–506. 2018.PubMed/NCBI
24	Tan J, Liu S, Jiang Q, Yu T and Huang K: lncRNA-MIAT increased in patients with coronary atherosclerotic heart disease. Cardiol Res Pract. 2019:62801942019. View Article : Google Scholar :
25	Liao J, Wang J, Liu Y, Li J and Duan L: Transcriptome sequencing of lncRNA, miRNA, mRNA and interaction network constructing in coronary heart disease. BMC Med Genomics. 12:1242019. View Article : Google Scholar
26	Lin XL, Hu HJ, Liu YB, Hu XM, Fan XJ, Zou WW, Pan YQ, Zhou WQ, Peng MW and Gu CH: Allicin induces the upregulation of ABCA1 expression via PPARγ/LXRα signaling in THP-1 macrophage-derived foam cells. Int J Mol Med. 39:1452–1460. 2017. View Article : Google Scholar : PubMed/NCBI
27	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar
28	Cui Y, Fu S, Sun D, Xing J, Hou T and Wu X: EPC-derived exosomes promote osteoclastogenesis through lncRNA-MALAT1. J Cell Mol Med. 23:3843–3854. 2019. View Article : Google Scholar : PubMed/NCBI
29	National Research Council Committee for the Update of the Guide for the Care and Use of Laboratory Animals: The National Academies Collection: Reports funded by National Institutes of Health. Guide for the Care and Use of Laboratory Animals. 8th edition. National Academies Press; Washington, DC: 2011
30	Shen S, Zheng X, Zhu Z, Zhao S, Zhou Q, Song Z, Wang G and Wang Z: Silencing of GAS5 represses the malignant progression of atherosclerosis through upregulation of miR-135a. Biomed Pharmacother. 118:1093022019. View Article : Google Scholar
31	Guo Z, Zhao Z, Yang C and Song C: Transfer of microRNA-221 from mesenchymal stem cell-derived extracellular vesicles inhibits atherosclerotic plaque formation. Transl Res. 226:83–95. 2020. View Article : Google Scholar : PubMed/NCBI
32	Yu XH, Zhang DW, Zheng XL and Tang CK: Cholesterol transport system: An integrated cholesterol transport model involved in atherosclerosis. Prog Lipid Res. 73:65–91. 2019. View Article : Google Scholar
33	Ertek S: High-density lipoprotein (HDL) dysfunction and the future of HDL. Curr Vasc Pharmacol. 16:490–498. 2018. View Article : Google Scholar
34	Kennedy MA, Barrera GC, Nakamura K, Baldán A, Tarr P, Fishbein MC, Frank J, Francone OL and Edwards PA: ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Cell Metab. 1:121–131. 2005. View Article : Google Scholar : PubMed/NCBI
35	Talbot CPJ, Plat J, Ritsch A and Mensink RP: Determinants of cholesterol efflux capacity in humans. Prog Lipid Res. 69:21–32. 2018. View Article : Google Scholar
36	Wang H, Yang Y, Sun X, Tian F, Guo S, Wang W, Tian Z, Jin H, Zhang Z and Tian Y: Sonodynamic therapy-induced foam cells apoptosis activates the phagocytic PPARγ-LXRα-ABCA1/ABCG1 pathway and promotes cholesterol efflux in advanced plaque. Theranostics. 8:4969–4984. 2018. View Article : Google Scholar :
37	Mao MJ, Hu JP, Wang C, Zhang YY and Liu P: Effects of Chinese herbal medicine Guanxinkang on expression of PPARγ-LXRα-ABCA1 pathway in ApoE-knockout mice with atherosclerosis. Zhong Xi Yi Jie He Xue Bao. 10:814–820. 2012.In Chinese. View Article : Google Scholar
38	Li Y, Shi G, Han Y, Shang H, Li H, Liang W, Zhao W, Bai L and Qin C: Therapeutic potential of human umbilical cord mesenchymal stem cells on aortic atherosclerotic plaque in a high-fat diet rabbit model. Stem Cell Res Ther. 12:4072021. View Article : Google Scholar : PubMed/NCBI
39	Kirwin T, Gomes A, Amin R, Sufi A, Goswami S and Wang B: Mechanisms underlying the therapeutic potential of mesenchymal stem cells in atherosclerosis. Regen Med. 16:669–682. 2021. View Article : Google Scholar : PubMed/NCBI
40	Hashem RM, Rashed LA, Abdelkader RM and Hashem KS: Stem cell therapy targets the neointimal smooth muscle cells in experimentally induced atherosclerosis: Involvement of intracellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM). Braz J Med Biol Res. 54:e108072021. View Article : Google Scholar : PubMed/NCBI
41	Zhang X, Huang F, Li W, Dang JL, Yuan J, Wang J, Zeng DL, Sun CX, Liu YY, Ao Q, et al: Human gingiva-derived mesenchymal stem cells modulate monocytes/macrophages and alleviate atherosclerosis. Front Immunol. 9:8782018. View Article : Google Scholar
42	Chen S, Zhou H, Zhang B and Hu Q: Exosomal miR-512-3p derived from mesenchymal stem cells inhibits oxidized low-density lipoprotein-induced vascular endothelial cells dysfunction via regulating Keap1. J Biochem Mol Toxicol. 35:1–11. 2021. View Article : Google Scholar
43	Yang Y, Ye Y, Su X, He J, Bai W and He X: MSCs-derived exosomes and neuroinflammation, neurogenesis and therapy of traumatic brain injury. Front Cell Neurosci. 11:552017. View Article : Google Scholar :
44	Yu C, Tang W, Lu R, Tao Y, Ren T and Gao Y: Human adipose-derived mesenchymal stem cells promote lymphocyte apoptosis and alleviate atherosclerosis via miR-125b1-3p/BCL11B signal axis. Ann Palliat Med. 10:2123–2133. 2021. View Article : Google Scholar
45	Wang H, Gong H, Liu Y and Feng L: Relationship between lncRNA-Ang362 and prognosis of patients with coronary heart disease after percutaneous coronary intervention. Biosci Rep. 40:BSR202015242020. View Article : Google Scholar : PubMed/NCBI
46	Mao Q, Liang XL, Zhang CL, Pang YH and Lu YX: lncRNA KLF3-AS1 in human mesenchymal stem cell-derived exosomes ameliorates pyroptosis of cardiomyocytes and myocardial infarction through miR-138-5p/Sirt1 axis. Stem Cell Res Ther. 10:3932019. View Article : Google Scholar :
47	Li H, Han S, Sun Q, Yao Y, Li S, Yuan C, Zhang B, Jing B, Wu J, Song Y and Wang H: Long non-coding RNA CDKN2B-AS1 reduces inflammatory response and promotes cholesterol efflux in atherosclerosis by inhibiting ADAM10 expression. Aging (Albany NY). 11:1695–1715. 2019. View Article : Google Scholar
48	Meng XD, Yao HH, Wang LM, Yu M, Shi S, Yuan ZX and Liu J: Knockdown of GAS5 inhibits atherosclerosis progression via reducing EZH2-mediated ABCA1 transcription in ApoE^−/− mice. Mol Ther Nucleic Acids. 19:84–96. 2020. View Article : Google Scholar
49	Zhang ZZ, Chen JJ, Deng WY, Yu XH and Tan WH: CTRP1 decreases ABCA1 expression and promotes lipid accumulation through the miR-4245p/FoxO1 pathway in THP-1 macrophage-derived foam cells. Cell Biol Int. Jul 20–2021, Epub ahead of print https://doi.org/10.1002/cbin.11666. View Article : Google Scholar
50	Moradi-Chaleshtori M, Shojaei S, Mohammadi-Yeganeh S and Hashemi SM: Transfer of miRNA in tumor-derived exosomes suppresses breast tumor cell invasion and migration by inducing M1 polarization in macrophages. Life Sci. 282:1198002021. View Article : Google Scholar : PubMed/NCBI
51	Zhao R, Feng J and He G: miR-613 regulates cholesterol efflux by targeting LXRα and ABCA1 in PPARγ activated THP-1 macrophages. Biochem Biophys Res Commun. 448:329–334. 2014. View Article : Google Scholar
52	Xu Y, Lai F, Xu Y, Wu Y, Liu Q, Li N, Wei Y, Feng T, Zheng Z, Jiang W, et al: Mycophenolic acid induces ATP-binding cassette transporter A1 (ABCA1) expression through the PPARγ-LXRα-ABCA1 pathway. Biochem Biophys Res Commun. 414:779–782. 2011. View Article : Google Scholar : PubMed/NCBI
53	Gu HF, Li N, Xu ZQ, Hu L, Li H, Zhang RJ, Chen RM, Zheng XL, Tang YL and Liao DF: Chronic unpredictable mild stress promotes atherosclerosis via HMGB1/TLR4-mediated downregulation of PPARγ/LXRα/ABCA1 in ApoE^−/− mice. Front Physiol. 10:1652019. View Article : Google Scholar
54	Wang S, Zhang X, Liu M, Luan H, Ji Y, Guo P and Wu C: Chrysin inhibits foam cell formation through promoting cholesterol efflux from RAW264.7 macrophages. Pharm Biol. 53:1481–1487. 2015. View Article : Google Scholar : PubMed/NCBI