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Circular RNA circ_0008896 contributes to oxidized low-density lipoprotein-induced aortic endothelial cell injury via targeting miR-188-3p/NOD2 axis

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Cell Stress and Chaperones Aims and scope

Abstract

We aimed to investigate the role and mechanism of circ_0008896 in Atherosclerosis (AS) by using oxidized low-density lipoprotein (ox-LDL)-induced human aortic endothelial cell (HAECs). Levels of genes and proteins were measured by quantitative real-time PCR and Western blot. Functional experiments, including enzyme-linked immunosorbent assay analysis, cell counting kit-8, 5-ethynyl-2’-deoxyuridine (EdU), flow cytometry, tube formation assays and the detection of reactive oxygen species (ROS), malondialdehyde (MDA) and superoxide dismutase (SOD) generation, were performed to investigate the role of circ_0008896 on ox-LDL-induced HAEC damage. Circ_0008896 was increased in AS patients and ox-LDL-stimulated HAECs. Functionally, circ_0008896 knockdown reversed ox-LDL-induced inflammatory response, oxidative stress, apoptosis as well as arrest of proliferation and angiogenesis in HAECs in vitro. Mechanistically, circ_0008896 functioned as a sponge for miR-188-3p to relieve the repression of miR-188-3p on its target NOD2. A series of rescue experiments showed that miR-188-3p inhibition attenuated the protective effects of circ_0008896 knockdown on ox-LDL-stimulated HAECs, and NOD2 overexpression abolished the beneficial action of miR-188-3p in the suppression of inflammatory response and oxidative stress, and the promotion of cell growth and angiogenesis in HAECs under ox-LDL treatment. Circ_0008896 silencing attenuates ox-LDL-induced inflammatory response, oxidative stress, and growth arrest in HAECs in vitro, adding further understanding for the pathogenesis of AS.

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References

  • Ahmadi A, Panahi Y, Johnston TP, Sahebkar A (2021) Antidiabetic drugs and oxidized low-density lipoprotein: A review of anti-atherosclerotic mechanisms. Pharmacol Res 172:105819

    Article  CAS  PubMed  Google Scholar 

  • Alagia A, Eritja R (2016) siRNA and RNAi optimization. Wiley Interdisciplinary Reviews RNA 7(3):316–329

    Article  CAS  PubMed  Google Scholar 

  • Bruikman CS, Stoekenbroek RM, Hovingh GK, Kastelein JP (2017) New Drugs for Atherosclerosis. Can J Cardiol 33(3):350–357

    Article  PubMed  Google Scholar 

  • Cai Y, Liang R, Xiao S, Huang Q, Zhu D, Shi GP, Ouyang Q, Yang M (2021) Circ_0088194 Promotes the Invasion and Migration of Rheumatoid Arthritis Fibroblast-Like Synoviocytes via the miR-766-3p/MMP2 Axis. Front Immunol 12:628654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen LL, Yang L (2015) Regulation of circRNA biogenesis. RNA Biol 12(4):381–388

    Article  PubMed  PubMed Central  Google Scholar 

  • Choy JC, Granville DJ, Hunt DW, McManus BM (2001) Endothelial cell apoptosis: biochemical characteristics and potential implications for atherosclerosis. J Mol Cell Cardiol 33(9):1673–1690

    Article  CAS  PubMed  Google Scholar 

  • Frohlich J, Al-Sarraf A (2013) Cardiovascular risk and atherosclerosis prevention. Cardiovasc Pathol 22(1):16–18

    Article  PubMed  Google Scholar 

  • Gu Y, Ma X, Li J, Ma Y, Zhang Y (2021) Identification of candidate targets for the diagnosis and treatment of atherosclerosis by bioinformatics analysis. Am J Transl Res 13(5):4137–4151

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hansen TB, Jensen TI, Clausen BH, Bramsen JB, Finsen B, Damgaard CK, Kjems J (2013) Natural RNA circles function as efficient microRNA sponges. Nature 495(7441):384–388

    Article  CAS  PubMed  Google Scholar 

  • He Q, Shao D, Hao S, Yuan Y, Liu H, Liu F, Mu Q (2021) CircSCAP Aggravates Oxidized Low-density Lipoprotein-induced Macrophage Injury by Upregulating PDE3B by miR-221-5p in Atherosclerosis. J Cardiovasc Pharmacol 78(5):e749–e760

    Article  CAS  PubMed  Google Scholar 

  • Hu F, Chen X, Gao J, Shen Y, Yang J (2021) CircDIP2C ameliorates oxidized low-density lipoprotein-induced cell dysfunction by binding to miR-556-5p to induce TET2 in human umbilical vein endothelial cells. Vascul Pharmacol 139:106887

    Article  CAS  PubMed  Google Scholar 

  • Ji N, Wang Y, Gong X, Ni S, Zhang H (2021) CircMTO1 inhibits ox-LDL-stimulated vascular smooth muscle cell proliferation and migration via regulating the miR-182-5p/RASA1 axis. Mol Med (cambridge, Mass) 27(1):73

    Article  CAS  Google Scholar 

  • Jia SJ, Gao KQ, Zhao M (2017) Epigenetic regulation in monocyte/macrophage: A key player during atherosclerosis. Cardiovasc Ther 35(3)

  • Kim HJ (2015) Role of Nucleotide-binding and Oligomerization Domain 2 Protein (NOD2) in the Development of Atherosclerosis. Korean J Physiol Pharmacol 19(6):479–484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kristensen LS, Andersen MS, Stagsted LVW, Ebbesen KK, Hansen TB, Kjems J (2019) The biogenesis, biology and characterization of circular RNAs. Nat Rev Genet 20(11):675–691

    Article  CAS  PubMed  Google Scholar 

  • Libby P, Bornfeldt KE, Tall AR (2016) Atherosclerosis: Successes, Surprises, and Future Challenges. Circ Res 118(4):531–534

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu HQ, Zhang XY, Edfeldt K, Nijhuis MO, Idborg H, Bäck M, Roy J, Hedin U, Jakobsson PJ, Laman JD et al (2013) NOD2-mediated innate immune signaling regulates the eicosanoids in atherosclerosis. Arterioscler Thromb Vasc Biol 33(9):2193–2201

    Article  CAS  PubMed  Google Scholar 

  • Marques-Rocha JL, Samblas M, Milagro FI, Bressan J, Martínez JA, Marti A (2015) Noncoding RNAs, cytokines, and inflammation-related diseases. FASEB J 29(9):3595–3611

    Article  CAS  PubMed  Google Scholar 

  • Mi S, Wang P, Lin L (2020) miR-188-3p Inhibits Vascular Smooth Muscle Cell Proliferation and Migration by Targeting Fibroblast Growth Factor 1 (FGF1). Med Sci Monit 26:e924394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Paone S, Baxter AA, Hulett MD, Poon IKH (2019) Endothelial cell apoptosis and the role of endothelial cell-derived extracellular vesicles in the progression of atherosclerosis. Cell Mol Life Sci 76(6):1093–1106

    Article  CAS  PubMed  Google Scholar 

  • Saaoud F, Drummer IVC, Shao Y, Sun Y, Lu Y, Xu K, Ni D, Jiang X, Wang H, Yang X (2021) Circular RNAs are a novel type of non-coding RNAs in ROS regulation, cardiovascular metabolic inflammations and cancers. Pharmacol Ther 220:107715

    Article  CAS  PubMed  Google Scholar 

  • Sahebkar A (2015) Dual effect of curcumin in preventing atherosclerosis: the potential role of pro-oxidant-antioxidant mechanisms. Nat Prod Res 29(6):491–492

    Article  CAS  PubMed  Google Scholar 

  • Sanz J, Fayad ZA (2008) Imaging of atherosclerotic cardiovascular disease. Nature 451(7181):953–957

    Article  CAS  PubMed  Google Scholar 

  • Suciu CF, Prete M, Ruscitti P, Favoino E, Giacomelli R, Perosa F (2018) Oxidized low density lipoproteins: The bridge between atherosclerosis and autoimmunity. Possible implications in accelerated atherosclerosis and for immune intervention in autoimmune rheumatic disorders. Autoimmun Rev17(4):366–375

  • Sun X, Deng K, Zang Y, Zhang Z, Zhao B, Fan J, Huang L (2021) Exploring the regulatory roles of circular RNAs in the pathogenesis of atherosclerosis. Vascul Pharmacol :106898

  • Thomson DW, Dinger ME (2016) Endogenous microRNA sponges: evidence and controversy. Nat Rev Genet 17(5):272–283

    Article  CAS  PubMed  Google Scholar 

  • Vo JN, Cieslik M, Zhang Y, Shukla S, Xiao L, Zhang Y, Wu YM, Dhanasekaran SM, Engelke CG, Cao X et al (2019) The Landscape of Circular RNA in Cancer. Cell 176(4):869-881.e813

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang X, Bai M (2021) CircTM7SF3 contributes to oxidized low-density lipoprotein-induced apoptosis, inflammation and oxidative stress through targeting miR-206/ASPH axis in atherosclerosis cell model in vitro. BMC Cardiovasc Disord 21(1):51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiong WC, Han N, Wu N, Zhao KL, Han C, Wang HX, Ping GF, Zheng PF, Feng H, Qin L et al (2018) Interplay between long noncoding RNA ZEB1-AS1 and miR-101/ZEB1 axis regulates proliferation and migration of colorectal cancer cells. Am J Transl Res 10(2):605–617

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yuan J, Usman A, Das T, Patterson AJ, Gillard JH, Graves MJ (2017) Imaging Carotid Atherosclerosis Plaque Ulceration: Comparison of Advanced Imaging Modalities and Recent Developments. AJNR Am J Neuroradiol 38(4):664–671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang XF, Yang Y, Yang XY, Tong Q (2018) MiR-188-3p upregulation results in the inhibition of macrophage proinflammatory activities and atherosclerosis in ApoE-deficient mice. Thromb Res 171:55–61

    Article  CAS  PubMed  Google Scholar 

  • Zhang MM, Bahal R, Rasmussen TP, Manautou JE, Zhong XB (2021) The growth of siRNA-based therapeutics: Updated clinical studies. Biochem Pharmacol 189:114432

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Heart Function Examination Room, the Second Hospital of Dalian Medical University, Dalian, China

    Liping Liu

  2. Department of Cardiology, the Second Hospital of Dalian Medical University, Dalian, China

    Yan Liu & Yueyan Zhao

  3. Dalian City, China

    Yueyan Zhao

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  1. Liping Liu
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  2. Yan Liu
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Contributions

Liping Liu designed and performed the research; Yan Liu and Yueyan Zhao analyzed the data; Liping Liu wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yueyan Zhao.

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Written informed consents were obtained from all participants and this study was permitted by the Ethics Committee of the Second Hospital of Dalian Medical Univercity.

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Liu, L., Liu, Y. & Zhao, Y. Circular RNA circ_0008896 contributes to oxidized low-density lipoprotein-induced aortic endothelial cell injury via targeting miR-188-3p/NOD2 axis. Cell Stress and Chaperones 28, 275–287 (2023). https://doi.org/10.1007/s12192-023-01336-x

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  • DOI: https://doi.org/10.1007/s12192-023-01336-x

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