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MicroRNA-221/222 regulate ox-LDL-induced endothelial apoptosis via Ets-1/p21 inhibition

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Abstract

Endothelial cells (ECs) apoptosis induced by oxidized low-density lipoprotein (ox-LDL) is thought to play an essential role in atherosclerosis. MicroRNAs (miRNAs) are a class of short non-coding RNAs, acting as posttranscriptional regulators of protein-coding genes involved in vascular cell biology. MiRNA-221 and miRNA-222 (miR-221/222) are known to be involved in the regulation of endothelial inflammation and angiogenesis. However, the function of miR-221/222 in ox-LDL-induced ECs apoptosis and atherosclerosis is still unknown. Here, we showed that miR-221/222 expression was markedly down-regulated in ox-LDL-induced apoptotic human umbilical cord vein endothelial cells. MiR-221/222 inhibition enhanced apoptosis in ECs, whereas over-expression of miR-221/222 could partly alleviate apoptotic cell death mediated by ox-LDL through suppression of Ets-1 and its downstream target p21. These findings suggest that manipulation of the miR-221/222-Ets-1-p21 pathway may offer a novel strategy for treatment of endothelial apoptosis and atherosclerosis.

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References

  1. 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

    CAS  PubMed  Google Scholar 

  2. Zhu H, Xia M, Hou M, Tang Z, Li Y, Ma J, Ling W (2005) Ox-LDL plays dual effect in modulating expression of inflammatory molecules through LOX-1 pathway in human umbilical vein endothelial cells. Front Biosci 10:2585–2594

    PubMed  Google Scholar 

  3. Heeba G, Hassan MK, Khalifa M, Malinski T (2007) Adverse balance of nitric oxide/peroxynitrite in the dysfunctional endothelium can be reversed by statins. J Cardiovasc Pharmacol 50(4):391–398

    CAS  PubMed  Google Scholar 

  4. Harada-Shiba M, Kinoshita M, Kamido H, Shimokado K (1998) Oxidized low density lipoprotein induces apoptosis in cultured human umbilical vein endothelial cells by common and unique mechanisms. J Biol Chem 273(16):9681–9687

    CAS  PubMed  Google Scholar 

  5. Ross R (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362(6423):801–809

    Article  CAS  PubMed  Google Scholar 

  6. Qin B, Yang H, Xiao B (2012) Role of microRNAs in endothelial inflammation and senescence. Mol Biol Rep 39(4):4509–4518

    CAS  PubMed  Google Scholar 

  7. Poliseno L, Tuccoli A, Mariani L, Evangelista M, Citti L, Woods K, Mercatanti A, Hammond S, Rainaldi G (2006) MicroRNAs modulate the angiogenic properties of HUVECs. Blood 108(9):3068–3071

    Article  CAS  PubMed  Google Scholar 

  8. Dentelli P, Rosso A, Orso F, Olgasi C, Taverna D, Brizzi MF (2010) microRNA-222 controls neovascularization by regulating signal transducer and activator of transcription 5A expression. Arterioscler Thromb Vasc Biol 30(8):1562–1568

    CAS  PubMed  Google Scholar 

  9. Chen Y, Banda M, Speyer CL, Smith JS, Rabson AB, Gorski DH (2010) Regulation of the expression and activity of the antiangiogenic homeobox gene GAX/MEOX2 by ZEB2 and microRNA-221. Mol Cell Biol 30(15):3902–3913

    PubMed Central  CAS  PubMed  Google Scholar 

  10. Zhu N, Zhang D, Chen S, Liu X, Lin L, Huang X, Guo Z, Liu J, Wang Y, Yuan W, Qin Y (2011) Endothelial enriched microRNAs regulate angiotensin II-induced endothelial inflammation and migration. Atherosclerosis 215(2):286–293

    Article  CAS  PubMed  Google Scholar 

  11. Garofalo M, Quintavalle C, Romano G, Croce CM, Condorelli G (2012) miR221/222 in cancer: their role in tumor progression and response to therapy. Curr Mol Med 12(1):27–33

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Qin B, Xiao B, Liang D, Xia J, Li Y, Yang H (2011) MicroRNAs expression in ox-LDL treated HUVECs: MiR-365 modulates apoptosis and Bcl-2 expression. Biochem Biophys Res Commun 410(1):127–133

    CAS  PubMed  Google Scholar 

  13. Zhang WW, Fang X, Mazur W, French BA, Georges RN, Roth JA (1994) High-efficiency gene transfer and high-level expression of wild-type p53 in human lung cancer cells mediated by recombinant adenovirus. Cancer Gene Ther 1(1):5–13

    PubMed  Google Scholar 

  14. 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. Vasc Pharmacol 47(1):1–9

    Google Scholar 

  15. Teruyama K, Abe M, Nakano T, Iwasaka-Yagi C, Takahashi S, Yamada S, Sato Y (2001) Role of transcription factor Ets-1 in the apoptosis of human vascular endothelial cells. J Cell Physiol 188(2):243–252

    CAS  PubMed  Google Scholar 

  16. Zhan Y, Brown C, Maynard E, Anshelevich A, Ni W, Ho IC, Oettgen P (2005) Ets-1 is a critical regulator of Ang II-mediated vascular inflammation and remodeling. J Clin Invest 115(9):2508–2516

    PubMed Central  CAS  PubMed  Google Scholar 

  17. Weber M, Kim S, Patterson N, Rooney K, Searles CD (2014) MiRNA-155 targets myosin light chain kinase and modulates actin cytoskeleton organization in endothelial cells. Am J Physiol Heart Circ Physiol 306(8):H1192–H1203

    PubMed Central  CAS  PubMed  Google Scholar 

  18. Fang Y, Davies PF (2012) Site-specific microRNA-92a regulation of Kruppel-like factors 4 and 2 in atherosusceptible endothelium. Arterioscler Thromb Vasc Biol 32(4):979–987

    PubMed Central  CAS  PubMed  Google Scholar 

  19. Suarez Y, Fernandez-Hernando C, Pober JS, Sessa WC (2007) Dicer dependent microRNAs regulate gene expression and functions in human endothelial cells. Circ Res 100(8):1164–1173

    CAS  PubMed  Google Scholar 

  20. Pu XX, Huang GL, Guo HQ, Guo CC, Li H, Ye S, Ling S, Jiang L, Tian Y, Lin TY (2010) Circulating miR-221 directly amplified from plasma is a potential diagnostic and prognostic marker of colorectal cancer and is correlated with p53 expression. J Gastroenterol Hepatol 25(10):1674–1680

    CAS  PubMed  Google Scholar 

  21. Altuvia Y, Landgraf P, Lithwick G, Elefant N, Pfeffer S, Aravin A, Brownstein MJ, Tuschl T, Margalit H (2005) Clustering and conservation patterns of human microRNAs. Nucleic Acids Res 33(8):2697–2706

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Wei Y, Schober A, Weber C (2013) Pathogenic arterial remodeling: the good and bad of microRNAs. Am J Physiol Heart Circ Physiol 304(8):H1050–H1059

    CAS  PubMed  Google Scholar 

  23. Sato Y (2001) Role of ETS family transcription factors in vascular development and angiogenesis. Cell Struct Funct 26(1):19–24

    CAS  PubMed  Google Scholar 

  24. Tokarz P, Blasiak J (2012) The role of microRNA in metastatic colorectal cancer and its significance in cancer prognosis and treatment. Acta Biochim Pol 59(4):467–474

    CAS  PubMed  Google Scholar 

  25. Piva R, Spandidos DA, Gambari R (2013) From microRNA functions to microRNA therapeutics: novel targets and novel drugs in breast cancer research and treatment (review). Int J Oncol 43(4):985–994

    PubMed Central  CAS  PubMed  Google Scholar 

  26. Shaikhibrahim Z, Wernert N (2012) ETS transcription factors and prostate cancer: the role of the family prototype ETS-1 (review). Int J Oncol 40(6):1748–1754

    CAS  PubMed  Google Scholar 

  27. Dejana E, Taddei A, Randi AM (2007) Foxs and Ets in the transcriptional regulation of endothelial cell differentiation and angiogenesis. Biochim Biophys Acta 1775(2):298–312

    CAS  PubMed  Google Scholar 

  28. Yoo HJ, Kim BR, Byun HJ, Park SY, Rho SB (2013) BLU enhances the effects of anti-angiogenic activity in combination with gemcitabine-based chemotherapeutic agents. Int J Biochem Cell Biol 45(7):1236–1245

    CAS  PubMed  Google Scholar 

  29. Nubel T, Damrot J, Roos WP, Kaina B, Fritz G (2006) Lovastatin protects human endothelial cells from killing by ionizing radiation without impairing induction and repair of DNA double-strand breaks. Clin Cancer Res 12(3 Pt 1):933–939

    PubMed  Google Scholar 

  30. Ho TC, Chen SL, Yang YC, Chen CY, Feng FP, Hsieh JW, Cheng HC, Tsao YP (2008) 15-deoxy-Delta (12,14)-prostaglandin J2 induces vascular endothelial cell apoptosis through the sequential activation of MAPKS and p53. J Biol Chem 283(44):30273–30288

    PubMed Central  CAS  PubMed  Google Scholar 

  31. Chen J, Huang X, Halicka D, Brodsky S, Avram A, Eskander J, Bloomgarden NA, Darzynkiewicz Z, Goligorsky MS (2006) Contribution of p16INK4a and p21CIP1 pathways to induction of premature senescence of human endothelial cells: permissive role of p53. Am J Physiol Heart Circ Physiol 290(4):H1575–H1586

    CAS  PubMed  Google Scholar 

  32. Chan WH, Wu HJ (2008) Methylglyoxal and high glucose co-treatment induces apoptosis or necrosis in human umbilical vein endothelial cells. J Cell Biochem 103(4):1144–1157

    CAS  PubMed  Google Scholar 

  33. Fu X, Wang Q, Chen J, Huang X, Chen X, Cao L, Tan H, Li W, Zhang L, Bi J, Su Q, Chen L (2011) Clinical significance of miR-221 and its inverse correlation with p27Kip(1) in hepatocellular carcinoma. Mol Biol Rep 38(5):3029–3035

    CAS  PubMed  Google Scholar 

  34. Matsui J, Wakabayashi T, Asada M, Yoshimatsu K, Okada M (2004) Stem cell factor/c-kit signaling promotes the survival, migration, and capillary tube formation of human umbilical vein endothelial cells. J Biol Chem 279(18):18600–18607

    CAS  PubMed  Google Scholar 

  35. Liu X, Cheng Y, Yang J, Xu L, Zhang C (2012) Cell-specific effects of miR-221/222 in vessels: molecular mechanism and therapeutic application. J Mol Cell Cardiol 52(1):245–255

    PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by the grants from the National Nature Science Foundation of China (No. 81271328).

Conflict of interest

The authors have no competing personal or financial interests.

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Authors and Affiliations

  1. Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou, 510630, Guangdong, People’s Republic of China

    Bing Qin & Zhengqi Lu

  2. Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China

    Yuze Cao, Huan Yang & Bo Xiao

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  1. Bing Qin
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  2. Yuze Cao
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  3. Huan Yang
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  4. Bo Xiao
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  5. Zhengqi Lu
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Correspondence to Zhengqi Lu.

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Qin, B., Cao, Y., Yang, H. et al. MicroRNA-221/222 regulate ox-LDL-induced endothelial apoptosis via Ets-1/p21 inhibition. Mol Cell Biochem 405, 115–124 (2015). https://doi.org/10.1007/s11010-015-2403-5

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  • DOI: https://doi.org/10.1007/s11010-015-2403-5

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