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MicroRNA-150 targets ELK1 and modulates the apoptosis induced by ox-LDL in endothelial cells

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Abstract

Atherosclerosis, a chronic inflammatory disease, is the major cause of life-threatening complications such as myocardial infarction and stroke. Endothelial cells (ECs) apoptosis plays a vital role in the initiation and progression of atherosclerosis. Although a subset of microRNAs (miRNAs) have been identified as critical regulators of atherosclerosis, studies on their participation in endothelial apoptosis in atherosclerosis have been limited. In the current study, we show that miRNA-150 (miR-150) expression was substantially up-regulated during the oxidized low-density lipoprotein (ox-LDL)-induced apoptosis in human umbilical cord vein endothelial cells (HUVECs). Forced expression of miR-150 enhanced apoptosis in ECs, whereas inhibition of miR-150 could partly alleviate apoptotic cell death mediated by ox-LDL. Further analysis identified ELK1 as a direct target of miR-150, and ELK1 knockdown abolished the anti-apoptotic effect of miR-150 inhibitor. These findings reveal a novel role of miR-150 in endothelial apoptosis and indicate a therapeutic potential of miR-150 for endothelial dysfunction and atherosclerosis.

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References

  1. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB, American Heart Association Statistics C and Stroke Statistics S (2015) Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation 131:e29–322. doi:10.1161/CIR.0000000000000152

    Article  PubMed  Google Scholar 

  2. Peng N, Meng N, Wang S, Zhao F, Zhao J, Su L, Zhang S, Zhang Y, Zhao B, Miao J (2014) An activator of mTOR inhibits oxLDL-induced autophagy and apoptosis in vascular endothelial cells and restricts atherosclerosis in apolipoprotein E(-)/(-) mice. Sci Rep 4:5519. doi:10.1038/srep05519

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Menghini R, Casagrande V, Marino A, Marchetti V, Cardellini M, Stoehr R, Rizza S, Martelli E, Greco S, Mauriello A, Ippoliti A, Martelli F, Lauro R, Federici M (2014) MiR-216a: a link between endothelial dysfunction and autophagy. Cell Death Dis 5:e1029. doi:10.1038/cddis.2013.556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Sima AV, Stancu CS, Simionescu M (2009) Vascular endothelium in atherosclerosis. Cell Tissue Res 335:191–203. doi:10.1007/s00441-008-0678-5

    Article  CAS  PubMed  Google Scholar 

  5. Durand E, Scoazec A, Lafont A, Boddaert J, Al Hajzen A, Addad F, Mirshahi M, Desnos M, Tedgui A, Mallat Z (2004) In vivo induction of endothelial apoptosis leads to vessel thrombosis and endothelial denudation: a clue to the understanding of the mechanisms of thrombotic plaque erosion. Circulation 109:2503–2506. doi:10.1161/01.CIR.0000130172.62481.90

    Article  CAS  PubMed  Google Scholar 

  6. Hung CH, Chan SH, Chu PM, Lin HC, Tsai KL (2016) Metformin regulates oxLDL-facilitated endothelial dysfunction by modulation of SIRT1 through repressing LOX-1-modulated oxidative signaling. Oncotarget 7:10773–10787. doi:10.18632/oncotarget.7387

    PubMed  PubMed Central  Google Scholar 

  7. Liu Y, Pan Q, Zhao Y, He C, Bi K, Chen Y, Zhao B, Chen Y, Ma X (2015) MicroRNA-155 regulates ROS production, NO generation, apoptosis and multiple functions of human brain microvessel endothelial cells under physiological and pathological conditions. J Cell Biochem 116:2870–2881. doi:10.1002/jcb.25234

    Article  CAS  PubMed  Google Scholar 

  8. Ahsan A, Han G, Pan J, Liu S, Padhiar AA, Chu P, Sun Z, Zhang Z, Sun B, Wu J, Irshad A, Lin Y, Peng J, Tang Z (2015) Phosphocreatine protects endothelial cells from oxidized low-density lipoprotein-induced apoptosis by modulating the PI3K/Akt/eNOS pathway. Apoptosis 20:1563–1576. doi:10.1007/s10495-015-1175-4

    Article  CAS  PubMed  Google Scholar 

  9. Ross R (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362:801–809. doi:10.1038/362801a0

    Article  CAS  PubMed  Google Scholar 

  10. Menghini R, Stohr R, Federici M (2014) MicroRNAs in vascular aging and atherosclerosis. Ageing Res Rev 17:68–78. doi:10.1016/j.arr.2014.03.005

    Article  CAS  PubMed  Google Scholar 

  11. Cao C, Zhang H, Zhao L, Zhou L, Zhang M, Xu H, Han X, Li G, Yang X, Jiang Y (2016) miR-125b targets DNMT3b and mediates p53 DNA methylation involving in the vascular smooth muscle cells proliferation induced by homocysteine. Exp Cell Res. doi:10.1016/j.yexcr.2016.07.007

    Google Scholar 

  12. Li X, Kong D, Chen H, Liu S, Hu H, Wu T, Wang J, Chen W, Ning Y, Li Y, Lu Z (2016) miR-155 acts as an anti-inflammatory factor in atherosclerosis-associated foam cell formation by repressing calcium-regulated heat stable protein 1. Sci Rep 6:21789. doi:10.1038/srep21789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bazan HA, Hatfield SA, O’Malley CB, Brooks AJ, Lightell D Jr, Woods TC (2015) Acute loss of miR-221 and miR-222 in the atherosclerotic plaque shoulder accompanies plaque rupture. Stroke 46:3285–3287. doi:10.1161/STROKEAHA.115.010567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yan B, Yao J, Liu JY, Li XM, Wang XQ, Li YJ, Tao ZF, Song YC, Chen Q, Jiang Q (2015) lncRNA-MIAT regulates microvascular dysfunction by functioning as a competing endogenous RNA. Circ Res 116:1143–1156. doi:10.1161/CIRCRESAHA.116.305510

    Article  CAS  PubMed  Google Scholar 

  15. Luo Z, Wen G, Wang G, Pu X, Ye S, Xu Q, Wang W, Xiao Q (2013) MicroRNA-200C and – 150 play an important role in endothelial cell differentiation and vasculogenesis by targeting transcription repressor ZEB1. Stem Cells 31:1749–1762. doi:10.1002/stem.1448

    Article  CAS  PubMed  Google Scholar 

  16. He QW, Li Q, Jin HJ, Zhi F, Suraj B, Zhu YY, Xia YP, Mao L, Chen XL, Hu B (2016) MiR-150 regulates poststroke cerebral angiogenesis via vascular endothelial growth factor in rats. CNS Neurosci Ther 22:507–517. doi:10.1111/cns.12525

    Article  CAS  PubMed  Google Scholar 

  17. Rajput C, Tauseef M, Farazuddin M, Yazbeck P, Amin MR, Avin Br V, Sharma T, Mehta D (2016) MicroRNA-150 suppression of angiopoetin-2 generation and signaling is crucial for resolving vascular injury. Arterioscler Thromb Vasc Biol 36:380–388. doi:10.1161/ATVBAHA.115.306997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chen XP, Xun KL, Wu Q, Zhang TT, Shi JS, Du GH (2007) Oxidized low density lipoprotein receptor-1 mediates oxidized low density lipoprotein-induced apoptosis in human umbilical vein endothelial cells: role of reactive oxygen species. Vascul Pharmacol 47:1–9. doi:10.1016/j.vph.2007.01.004

    Article  PubMed  Google Scholar 

  19. Wang Z, Liu J, Chen S, Wang Y, Cao L, Zhang Y, Kang W, Li H, Gui Y, Chen S, Ding J (2011) DJ-1 modulates the expression of Cu/Zn-superoxide dismutase-1 through the Erk1/2-Elk1 pathway in neuroprotection. Ann Neurol 70:591–599. doi:10.1002/ana.22514

    Article  CAS  PubMed  Google Scholar 

  20. Ding Z, Liu S, Wang X, Khaidakov M, Dai Y, Mehta JL (2013) Oxidant stress in mitochondrial DNA damage, autophagy and inflammation in atherosclerosis. Sci Rep 3:1077. doi:10.1038/srep01077

    PubMed  PubMed Central  Google Scholar 

  21. Dimmeler S, Haendeler J, Galle J, Zeiher AM (1997) Oxidized low-density lipoprotein induces apoptosis of human endothelial cells by activation of CPP32-like proteases. A mechanistic clue to the ‘response to injury’ hypothesis. Circulation 95:1760–1763

    Article  CAS  PubMed  Google Scholar 

  22. Zhou Y, Li XH, Zhang CC, Wang MJ, Xue WL, Wu DD, Ma FF, Li WW, Tao BB, Zhu YC (2016) Hydrogen sulfide promotes angiogenesis by downregulating miR-640 via the VEGFR2/mTOR pathway. Am J Physiol Cell Physiol 310:C305–C317. doi:10.1152/ajpcell.00230.2015

    Article  PubMed  Google Scholar 

  23. Hartmann P, Zhou Z, Natarelli L, Wei Y, Nazari-Jahantigh M, Zhu M, Grommes J, Steffens S, Weber C, Schober A (2016) Endothelial Dicer promotes atherosclerosis and vascular inflammation by miRNA-103-mediated suppression of KLF4. Nat Commun 7:10521. doi:10.1038/ncomms10521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Schober A, Weber C (2016) Mechanisms of microRNAs in atherosclerosis. Annu Rev Pathol 11:583–616. doi:10.1146/annurev-pathol-012615-044135

    Article  CAS  PubMed  Google Scholar 

  25. He Y, Jiang X, Chen J (2014) The role of miR-150 in normal and malignant hematopoiesis. Oncogene 33:3887–3893. doi:10.1038/onc.2013.346

    Article  CAS  PubMed  Google Scholar 

  26. Wang W, Wang X, Zhang Y, Wang D, Gao H, Wang L, Gao S (2016) Prognostic role of microRNA-150 in various carcinomas: a meta-analysis. Onco Targets Ther 9: 1371–1379. doi:10.2147/OTT.S97969

    Article  PubMed  PubMed Central  Google Scholar 

  27. Liu CH, Sun Y, Li J, Gong Y, Tian KT, Evans LP, Morss PC, Fredrick TW, Saba NJ, Chen J (2015) Endothelial microRNA-150 is an intrinsic suppressor of pathologic ocular neovascularization. Proc Natl Acad Sci USA 112:12163–12168. doi:10.1073/pnas.1508426112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fang Z, He QW, Li Q, Chen XL, Baral S, Jin HJ, Zhu YY, Li M, Xia YP, Mao L, Hu B (2016) MicroRNA-150 regulates blood–brain barrier permeability via Tie-2 after permanent middle cerebral artery occlusion in rats. FASEB J 30:2097–2107. doi:10.1096/fj.201500126

    Article  CAS  PubMed  Google Scholar 

  29. Galle J, Heinloth A, Wanner C, Heermeier K (2001) Dual effect of oxidized LDL on cell cycle in human endothelial cells through oxidative stress. Kidney Int Suppl 78:S120–S123. doi:10.1046/j.1523-1755.2001.59780120.x

    Article  CAS  PubMed  Google Scholar 

  30. Sharrocks AD (2001) The ETS-domain transcription factor family. Nat Rev Mol Cell Biol 2:827–837. doi:10.1038/35099076

    Article  CAS  PubMed  Google Scholar 

  31. Zhang X, Zhang B, Gao J, Wang X, Liu Z (2013) Regulation of the microRNA 200b (miRNA-200b) by transcriptional regulators PEA3 and ELK-1 protein affects expression of Pin1 protein to control anoikis. J Biol Chem 288:32742–32752. doi:10.1074/jbc.M113.478016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Laliotis A, Vrekoussis T, Kafousi M, Sanidas E, Askoxilakis J, Melissas J, Mavroudis D, Castanas E, Stathopoulos EN (2013) Immunohistochemical study of pElk-1 expression in human breast cancer: association with breast cancer biologic profile and clinicopathologic features. Breast 22:89–95. doi:10.1016/j.breast.2012.09.013

    Article  PubMed  Google Scholar 

  33. Morris JF, Sul JY, Kim MS, Klein-Szanto AJ, Schochet T, Rustgi A, Eberwine JH (2013) Elk-1 phosphorylated at threonine-417 is present in diverse cancers and correlates with differentiation grade of colonic adenocarcinoma. Hum Pathol 44:766–776. doi:10.1016/j.humpath.2012.08.001

    Article  CAS  PubMed  Google Scholar 

  34. Kawahara T, Aljarah AK, Shareef HK, Inoue S, Ide H, Patterson JD, Kashiwagi E, Han B, Li Y, Zheng Y, Miyamoto H (2016) Silodosin inhibits prostate cancer cell growth via ELK1 inactivation and enhances the cytotoxic activity of gemcitabine. Prostate 76:744–756. doi:10.1002/pros.23164

    Article  CAS  PubMed  Google Scholar 

  35. Lee SY, Choi HC, Choe YJ, Shin SJ, Lee SH, Kim HS (2014) Nutlin-3 induces BCL2A1 expression by activating ELK1 through the mitochondrial p53-ROS-ERK1/2 pathway. Int J Oncol 45:675–682. doi:10.3892/ijo.2014.2463

    CAS  PubMed  Google Scholar 

  36. Chamorro-Jorganes A, Lee MY, Araldi E, Landskroner-Eiger S, Fernandez-Fuertes M, Sahraei M, Quiles Del Rey M, van Solingen C, Yu J, Fernandez-Hernando C, Sessa WC, Suarez Y (2016) VEGF-induced expression of miR-17-92 cluster in endothelial cells is mediated by ERK/ELK1 activation and regulates angiogenesis. Circ Res 118:38–47. doi:10.1161/CIRCRESAHA.115.307408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Edinger AL, Thompson CB (2004) Death by design: apoptosis, necrosis and autophagy. Curr Opin Cell Biol 16:663–669. doi:10.1016/j.ceb.2004.09.011

    Article  CAS  PubMed  Google Scholar 

  38. Duprez L, Wirawan E, Vanden Berghe T, Vandenabeele P (2009) Major cell death pathways at a glance. Microbes Infect 11:1050–1062. doi:10.1016/j.micinf.2009.08.013

    Article  CAS  PubMed  Google Scholar 

  39. Napoli C (2003) Oxidation of LDL, atherogenesis, and apoptosis. Ann N Y Acad Sci 1010:698–709

    Article  CAS  PubMed  Google Scholar 

  40. Yang K, He M, Cai Z, Ni C, Deng J, Ta N, Xu J, Zheng J (2015) A decrease in miR-150 regulates the malignancy of pancreatic cancer by targeting c-Myb and MUC4. Pancreas 44:370–379. doi:10.1097/MPA.0000000000000283

    Article  CAS  PubMed  Google Scholar 

  41. Yokobori T, Suzuki S, Tanaka N, Inose T, Sohda M, Sano A, Sakai M, Nakajima M, Miyazaki T, Kato H, Kuwano H (2013) MiR-150 is associated with poor prognosis in esophageal squamous cell carcinoma via targeting the EMT inducer ZEB1. Cancer Sci 104:48–54. doi:10.1111/cas.12030

    Article  CAS  PubMed  Google Scholar 

  42. Magenta A, Cencioni C, Fasanaro P, Zaccagnini G, Greco S, Sarra-Ferraris G, Antonini A, Martelli F, Capogrossi MC (2011) miR-200c is upregulated by oxidative stress and induces endothelial cell apoptosis and senescence via ZEB1 inhibition. Cell Death Differ 18:1628–1639. doi:10.1038/cdd.2011.42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Papa L, Manfredi G, Germain D (2014) SOD1, an unexpected novel target for cancer therapy. Genes Cancer 5:15–21. doi:10.18632/genesandcancer.4

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Fujimura M, Morita-Fujimura Y, Noshita N, Sugawara T, Kawase M, Chan PH (2000) The cytosolic antioxidant copper/zinc-superoxide dismutase prevents the early release of mitochondrial cytochrome c in ischemic brain after transient focal cerebral ischemia in mice. J Neurosci 20:2817–2824

    CAS  PubMed  Google Scholar 

  45. Narasimhan P, Liu J, Song YS, Massengale JL, Chan PH (2009) VEGF Stimulates the ERK 1/2 signaling pathway and apoptosis in cerebral endothelial cells after ischemic conditions. Stroke 40:1467–1473. doi:10.1161/STROKEAHA.108.534644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Holvoet P, Davey PC, De Keyzer D, Doukoure M, Deridder E, Bochaton-Piallat ML, Gabbiani G, Beaufort E, Bishay K, Andrieux N, Benhabiles N, Marguerie G (2006) Oxidized low-density lipoprotein correlates positively with toll-like receptor 2 and interferon regulatory factor-1 and inversely with superoxide dismutase-1 expression: studies in hypercholesterolemic swine and THP-1 cells. Arterioscler Thromb Vasc Biol 26:1558–1565. doi:10.1161/01.ATV.0000226553.01555.02

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by a grant from the Medical Scientific Research Foundation of Guangdong Province, China (No. A2016059).

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Correspondence to Zhengqi Lu.

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Qin, B., Shu, Y., Xiao, L. et al. MicroRNA-150 targets ELK1 and modulates the apoptosis induced by ox-LDL in endothelial cells. Mol Cell Biochem 429, 45–58 (2017). https://doi.org/10.1007/s11010-016-2935-3

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  • DOI: https://doi.org/10.1007/s11010-016-2935-3

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