IRF2BP2 prevents ox‑LDL‑induced inflammation and EMT in endothelial cells via regulation of KLF2

Jiang,Yongri; Shen,Qiuling

doi:10.3892/etm.2021.9912

IRF2BP2 prevents ox‑LDL‑induced inflammation and EMT in endothelial cells via regulation of KLF2

Authors:
- Yongri Jiang
- Qiuling Shen
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Affiliations: Department of Cardiovascular Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China, Department of Laboratory Diagnosis, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
Published online on: March 12, 2021 https://doi.org/10.3892/etm.2021.9912
Article Number: 481
Copyright: © Jiang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Oxidized low‑density lipoprotein (ox‑LDL)‑induced endothelial dysfunction contributes to the progression of atherosclerosis. Interferon regulatory factor 2‑binding protein 2 (IRF2BP2) attenuates macrophage‑mediated inflammation and susceptibility to atherosclerosis. However, the effects of IRF2BP2 on vascular endothelial cells in atherosclerosis have not been fully elucidated. In the present study, the effects of IRF2BP2 on cell viability, inflammation and endothelial‑to‑mesenchymal transition (EMT) of human umbilical vein endothelial cells (HUVECs) were assessed using Cell Counting Kit‑8 (CCK‑8) assays, ELISA kits and western blot analysis, respectively. In addition, the expression levels of Krüppel‑like factor 2 (KLF2) were determined by reverse transcription‑quantitative PCR and immunofluorescence assays. A Nitrate/Nitrite assay kit was utilized to detect the production of nitric oxide (NO). The results demonstrated that ox‑LDL induced inflammation and EMT of HUVECs, and decreased the NO levels. Furthermore, IRF2BP2 overexpression protected HUVECs against ox‑LDL‑induced inflammation, EMT and endothelial dysfunction, and resulted in upregulated expression of KLF2. Additionally, IRF2BP2 was shown to bind to KLF2, and KLF2 knockdown reversed the protective effects of IRF2BP2 on ox‑LDL‑exposed HUVECs. These findings indicated that IRF2BP2 may prevent ox‑LDL‑induced endothelial damage via upregulating KLF2 expression.

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1	Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL, Cooney MT, Corrà U, Cosyns B, Deaton C, et al: 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 37:2315–2381. 2016.PubMed/NCBI View Article : Google Scholar
2	Mauricio MD, Aldasoro M, Ortega J and Vila JM: Endothelial dysfunction in morbid obesity. Curr Pharm Des. 19:5718–5729. 2013.PubMed/NCBI View Article : Google Scholar
3	Vanhoutte PM, Shimokawa H, Tang EH and Feletou M: Endothelial dysfunction and vascular disease. Acta Physiol (Oxf). 196:193–222. 2009.PubMed/NCBI View Article : Google Scholar
4	Molinaro R, Boada C, Del Rosal GM, Hartman KA, Corbo C, Andrews ED, Toledano-Furman NE, Cooke JP and Tasciotti E: Vascular inflammation: A novel access route for nanomedicine. Methodist Debakey Cardiovasc J. 12:169–174. 2016.PubMed/NCBI View Article : Google Scholar
5	Seneviratne AN and Monaco C: Role of inflammatory cells and toll-like receptors in atherosclerosis. Curr Vasc Pharmacol. 13:146–160. 2015.PubMed/NCBI View Article : Google Scholar
6	Hansson GK: Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med. 352:1685–1695. 2005.PubMed/NCBI View Article : Google Scholar
7	Packard CJ: LDL cholesterol: How low to go? Trends Cardiovasc Med. 28:348–354. 2018.PubMed/NCBI View Article : Google Scholar
8	Bäck M and Hansson GK: Anti-inflammatory therapies for atherosclerosis. Nat Rev Cardiol. 12:199–211. 2015.PubMed/NCBI View Article : Google Scholar
9	Childs KS and Goodbourn S: Identification of novel co-repressor molecules for interferon regulatory factor-2. Nucleic Acids Res. 31:3016–3026. 2003.PubMed/NCBI View Article : Google Scholar
10	Carneiro FR, Ramalho-Oliveira R, Mognol GP and Viola JP: Interferon regulatory factor 2 binding protein 2 is a new NFAT1 partner and represses its transcriptional activity. Mol Cell Biol. 31:2889–2901. 2011.PubMed/NCBI View Article : Google Scholar
11	Stadhouders R, Cico A, Stephen T, Thongjuea S, Kolovos P, Baymaz HI, Yu X, Demmers J, Bezstarosti K, Maas A, et al: Control of developmentally primed erythroid genes by combinatorial co-repressor actions. Nat Commun. 6(8893)2015.PubMed/NCBI View Article : Google Scholar
12	Li T, Luo Q, He L, Li D, Li Q, Wang C, Xie J and Yi C: Interferon regulatory factor-2 binding protein 2 ameliorates sepsis-induced cardiomyopathy via AMPK-mediated anti-inflammation and anti-apoptosis. Inflammation. 43:1464–1475. 2020.PubMed/NCBI View Article : Google Scholar
13	Ma YL, Xia JL and Gao X: Suppressing Irf2bp2 expressions accelerates metabolic syndrome-associated brain injury and hepatic dyslipidemia. Biochem Biophys Res Commun. 503:1651–1658. 2018.PubMed/NCBI View Article : Google Scholar
14	Chen HH, Keyhanian K, Zhou X, Vilmundarson RO, Almontashiri NA, Cruz SA, Pandey NR, Lerma Yap N, Ho T, Stewart CA, et al: IRF2BP2 reduces macrophage inflammation and susceptibility to atherosclerosis. Circ Res. 117:671–683. 2015.PubMed/NCBI View Article : Google Scholar
15	Jha P and Das H: KLF2 in regulation of NF-κB-mediated immune cell function and inflammation. Int J Mol Sci. 18(2383)2017.PubMed/NCBI View Article : Google Scholar
16	Zhou Z, Tang AT, Wong WY, Bamezai S, Goddard LM, Shenkar R, Zhou S, Yang J, Wright AC, Foley M, et al: Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling. Nature. 532:122–126. 2016.PubMed/NCBI View Article : Google Scholar
17	Wu W, Geng P, Zhu J, Li JW, Zhang L, Chen WL, Zhang DF, Lu Y and Xu XH: KLF2 regulates eNOS uncoupling via Nrf2/HO-1 in endothelial cells under hypoxia and reoxygenation. Chem Biol Interact. 305:105–111. 2019.PubMed/NCBI View Article : Google Scholar
18	Das H, Kumar A, Lin Z, Patino WD, Hwang PM, Feinberg MW, Majumder PK and Jain MK: Kruppel-like factor 2 (KLF2) regulates proinflammatory activation of monocytes. Proc Natl Acad Sci USA. 103:6653–6658. 2006.PubMed/NCBI View Article : Google Scholar
19	Zhuang T, Liu J, Chen X, Zhang L, Pi J, Sun H, Li L, Bauer R, Wang H, Yu Z, et al: Endothelial Foxp1 suppresses atherosclerosis via modulation of Nlrp3 inflammasome activation. Circ Res. 125:590–605. 2019.PubMed/NCBI View Article : Google Scholar
20	Zhao D, Sun X, Lv S, Sun M, Guo H, Zhai Y, Wang Z, Dai P, Zheng L, Ye M and Wang X: Salidroside attenuates oxidized low-density lipoprotein-induced endothelial cell injury via promotion of the AMPK/SIRT1 pathway. Int J Mol Med. 43:2279–2290. 2019.PubMed/NCBI View Article : Google Scholar
21	Lee WJ, Ou HC, Hsu WC, Chou MM, Tseng JJ, Hsu SL, Tsai KL and Sheu WHH: Ellagic acid inhibits oxidized LDL-mediated LOX-1 expression, ROS generation, and inflammation in human endothelial cells. J Vasc Surg. 52:1290–1300. 2010.PubMed/NCBI View Article : Google Scholar
22	Li H, Zhao Q, Chang L, Wei C, Bei H, Yin Y, Chen M, Wang H, Liang J and Wu Y: LncRNA MALAT1 modulates ox-LDL induced EndMT through the Wnt/β-catenin signaling pathway. Lipids Health Dis. 18(62)2019.PubMed/NCBI View Article : Google Scholar
23	Cybulsky MI, Iiyama K, Li H, Zhu S, Chen M, Iiyama M, Davis V, Gutierrez-Ramos JC, Connelly PW and Milstone DS: A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest. 107:1255–1262. 2001.PubMed/NCBI View Article : Google Scholar
24	Galkina E and Ley K: Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol. 27:2292–2301. 2007.PubMed/NCBI View Article : Google Scholar
25	Huang PL: Endothelial nitric oxide synthase and endothelial dysfunction. Curr Hypertens Rep. 5:473–480. 2003.PubMed/NCBI View Article : Google Scholar
26	Lyons D: Impairment and restoration of nitric oxide-dependent vasodilation in cardiovascular disease. Int J Cardiol. 62 (Suppl 2):S101–S109. 1997.PubMed/NCBI View Article : Google Scholar
27	Skuratovskaia D, Vulf M, Komar A, Kirienkova E and Litvinova L: Promising directions in atherosclerosis treatment based on epigenetic regulation using MicroRNAs and long noncoding RNAs. Biomolecules. 9(226)2019.PubMed/NCBI View Article : Google Scholar
28	Zhao Y, Evans MA, Allison MA, Bertoni AG, Budoff MJ, Criqui MH, Malik S, Ouyang P, Polak JF and Wong ND: Multisite atherosclerosis in subjects with metabolic syndrome and diabetes and relation to cardiovascular events: The multi-ethnic study of atherosclerosis. Atherosclerosis. 282:202–209. 2019.PubMed/NCBI View Article : Google Scholar
29	Gimbrone MA Jr and García-Cardeña G: Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res. 118:620–636. 2016.PubMed/NCBI View Article : Google Scholar
30	Zhang Y, Mu Q, Zhou Z, Song H, Zhang Y, Wu F, Jiang M, Wang F, Zhang W, Li L, et al: Protective effect of irisin on atherosclerosis via suppressing oxidized low density lipoprotein induced vascular inflammation and endothelial dysfunction. PLoS One. 11(e0158038)2016.PubMed/NCBI View Article : Google Scholar
31	Yang H, Mohamed AS and Zhou SH: Oxidized low density lipoprotein, stem cells, and atherosclerosis. Lipids Health Dis. 11(85)2012.PubMed/NCBI View Article : Google Scholar
32	Chen PY, Qin L, Baeyens N, Li G, Afolabi T, Budatha M, Tellides G, Schwartz MA and Simons M: Endothelial-to-mesenchymal transition drives atherosclerosis progression. J Clin Invest. 125:4514–4528. 2015.PubMed/NCBI View Article : Google Scholar
33	Kim I, Kim JH, Kim K, Seong S and Kim N: The IRF2BP2-KLF2 axis regulates osteoclast and osteoblast differentiation. BMB Rep. 52:469–474. 2019.PubMed/NCBI View Article : Google Scholar
34	Atkins GB, Wang Y, Mahabeleshwar GH, Shi H, Gao H, Kawanami D, Natesan V, Lin Z, Simon DI and Jain MK: Hemizygous deficiency of Krüppel-like factor 2 augments experimental atherosclerosis. Circ Res. 103:690–693. 2008.PubMed/NCBI View Article : Google Scholar
35	Xu Y, Liu P, Xu S, Koroleva M, Zhang S, Si S and Jin ZG: Tannic acid as a plant-derived polyphenol exerts vasoprotection via enhancing KLF2 expression in endothelial cells. Sci Rep. 7(6686)2017.PubMed/NCBI View Article : Google Scholar
36	Novodvorsky P and Chico TJ: The role of the transcription factor KLF2 in vascular development and disease. Prog Mol Biol Transl Sci. 124:155–188. 2014.PubMed/NCBI View Article : Google Scholar