Journal of Cardiovascular Translational Research

, Volume 6, Issue 6, pp 924–930 | Cite as

MicroRNAs in Endothelial Senescence and Atherosclerosis

  • Rossella Menghini
  • Viviana Casagrande
  • Massimo Federici
Article

Abstract

Aging is an important risk factor for the development of many cardiovascular diseases as atherosclerosis and is accompanied by the decline of endothelial function. Senescence of endothelial cells has been proposed to be involved in endothelial dysfunction and atherogenesis. Therefore, the study of new target therapies to prevent or reverse this process represents a field of great interest. MicroRNAs (miRNAs), a class of short RNAs, play key roles in various biological processes and in the development of human disease through specific posttranscriptional downregulation of gene expression. In particular, miRNAs that are highly expressed by endothelial cells can be detected in high concentration in human atherosclerotic plaques and in the circulation, suggesting their potential translation to bedside to determine the dysfunction of specific signaling pathways which play a role in coronary artery disease in the individual patient, a path towards a stratified medicine approach for early preventive treatment of disease. Here, we review the most recent advances in the field of atherosclerosis that implicate a role for miRNAs with a special emphasis on endothelial senescence and its involvement in the atherosclerotic process. Finally, we briefly discuss the potential use of miRNAs signatures to map atherosclerosis progression and in particular underlying the relevance of circulating plasma miRNAs that can be used clinically as biomarkers of vascular pathology.

Keywords

MicroRNA Endothelial dysfunction Cellular senescence Atherosclerosis 

References

  1. 1.
    Davignon, J., & Ganz, P. (2004). Role of endothelial dysfunction in atherosclerosis. Circulation, 109, III27–III32.PubMedCrossRefGoogle Scholar
  2. 2.
    Kim, V. N. (2005). MicroRNA biogenesis: coordinated cropping and dicing. Nature Reviews Molecular Cell Biology, 6, 376–385.PubMedCrossRefGoogle Scholar
  3. 3.
    Krützfeldt, J., & Stoffel, M. (2006). MicroRNAs: a new class of regulatory genes affecting metabolism. Cell Metabolism, 4, 9–12.PubMedCrossRefGoogle Scholar
  4. 4.
    Krützfeldt, J., Poy, M. N., & Stoffel, M. (2006). Strategies to determine the biological function of microRNAs. Nature Genetics, 38, S14–S19.PubMedCrossRefGoogle Scholar
  5. 5.
    Vasudevan, S., Tong, Y., & Steitz, J. A. (2007). Switching from repression to activation: microRNAs can up-regulate translation. Science, 318, 1931–1934.PubMedCrossRefGoogle Scholar
  6. 6.
    Minamino, T., & Komuro, I. (2007). Vascular cell senescence: contribution to atherosclerosis. Circulation Research, 100, 15–26.PubMedCrossRefGoogle Scholar
  7. 7.
    Minamino, T., Miyauchi, H., Yoshida, T., Ishida, Y., Yoshida, H., & Komuro, I. (2002). Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation, 105, 1541–1544.PubMedCrossRefGoogle Scholar
  8. 8.
    Fridman, A. L., & Tainsky, M. A. (2008). Critical pathways in cellular senescence and immortalization revealed by gene expression profiling. Oncogene, 27, 5975–5987.PubMedCrossRefGoogle Scholar
  9. 9.
    Gorospe, M., & Abdelmohsen, K. (2011). Microregulators come of age in senescence. Trends in Genetics, 27, 233–241.PubMedCrossRefGoogle Scholar
  10. 10.
    Kuehbacher, A., Urbich, C., Zeiher, A. M., & Dimmeler, S. (2007). Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis. Circulation Research, 101, 59–68.PubMedCrossRefGoogle Scholar
  11. 11.
    Suárez, Y., Fernández-Hernando, C., Pober, J. S., & Sessa, W. C. (2007). Dicer dependent microRNAs regulate gene expression and functions in human endothelial cells. Circulation Research, 100, 1164–1173.PubMedCrossRefGoogle Scholar
  12. 12.
    Ji, R., Cheng, Y., Yue, J., Yang, J., Liu, X., Chen, H., et al. (2007). MicroRNA expression signature and antisense-mediated depletion reveal an essential role of microRNA in vascular neointimal lesion formation. Circulation Research, 100, 1579–1588.PubMedCrossRefGoogle Scholar
  13. 13.
    Weber, C., & Noels, H. (2011). Atherosclerosis: current pathogenesis and therapeutic options. Nature Medicine, 17, 1410–1422.PubMedCrossRefGoogle Scholar
  14. 14.
    Kong, W., Zhao, J. J., He, L., & Cheng, J. Q. (2009). Strategies for profiling microRNA expression. Journal of Cellular Physiology, 218, 22–25.PubMedCrossRefGoogle Scholar
  15. 15.
    Menghini, R., Casagrande, V., Cardellini, M., Martelli, E., Terrinoni, A., Amati, F., et al. (2009). MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1. Circulation, 120, 1524–1532.PubMedCrossRefGoogle Scholar
  16. 16.
    Ito, T., Yagi, S., & Yamakuchi, M. (2010). MicroRNA-34a regulation of endothelial senescence. Biochemical and Biophysical Research Communications, 398, 735–740.PubMedCrossRefGoogle Scholar
  17. 17.
    Haigis, M. C., & Guarente, L. P. (2006). Mammalian sirtuins-emerging roles in physiology, aging, and calorie restriction. Genes & Development, 20, 2913–2921.CrossRefGoogle Scholar
  18. 18.
    Mattagajasingh, I., Kim, C. S., Naqvi, A., Yamamori, T., Hoffman, T. A., Jung, S. B., et al. (2007). SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proceedings of the National Academy of Sciences of the United States of America, 104, 14855–14860.PubMedCrossRefGoogle Scholar
  19. 19.
    Langley, E., Pearson, M., Faretta, M., Bauer, U. M., Frye, R. A., Minucci, S., et al. (2002). Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence. EMBO Journal, 21, 2383–2396.PubMedCrossRefGoogle Scholar
  20. 20.
    Alcendor, R. R., Gao, S., Zhai, P., Zablocki, D., Holle, E., Yu, X., et al. (2007). Sirt1 regulates aging and resistance to oxidative stress in the heart. Circulation Research, 100, 1512–1521.PubMedCrossRefGoogle Scholar
  21. 21.
    Vasa-Nicotera, M., Chen, H., Tucci, P., Yang, A. L., Saintigny, G., Menghini, R., et al. (2011). MiR-146a is modulated in human endothelial cell with aging. Atherosclerosis, 217, 326–330.PubMedCrossRefGoogle Scholar
  22. 22.
    LaRocca, T. J., Henson, G. D., Thorburn, A., Sindler, A. L., Pierce, G. L., & Seals, D. R. (2012). Translational evidence that impaired autophagy contributes to arterial ageing. Journal de Physiologie, 590, 3305–3316.CrossRefGoogle Scholar
  23. 23.
    Gibbings, D., Mostowy, S., Jay, F., Schwab, Y., Cossart, P., & Voinnet, O. (2012). Selective autophagy degrades DICER and AGO2 and regulates miRNA activity. Nature Cell Biology, 14, 1314–1321.PubMedCrossRefGoogle Scholar
  24. 24.
    Lee, I. H., Cao, L., Mostoslavsky, R., Lombard, D. B., Liu, J., Bruns, N. E., et al. (2008). A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proceedings of the National Academy of Sciences of the United States of America, 105, 3374–3379.PubMedCrossRefGoogle Scholar
  25. 25.
    Federici, M., Hribal, M. L., Menghini, R., Kanno, H., Marchetti, V., Porzio, O., et al. (2005). Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha. The Journal of Clinical Investigation, 115, 3494–3505.PubMedCrossRefGoogle Scholar
  26. 26.
    Menghini, R., Menini, S., Amoruso, R., Fiorentino, L., Casagrande, V., Marzano, V., et al. (2009). Tissue inhibitor of metalloproteinase 3 deficiency causes hepatic steatosis and adipose tissue inflammation in mice. Gastroenterology, 136, 663–672.PubMedCrossRefGoogle Scholar
  27. 27.
    Cardellini, M., Menghini, R., Luzi, A., Davato, F., Cardolini, I., D’Alfonso, R., et al. (2011). Decreased IRS2 and TIMP3 expression in monocytes from offspring of type 2 diabetic patients is correlated with insulin resistance and increased intima–media thickness. Diabetes, 60, 3265–3270.PubMedCrossRefGoogle Scholar
  28. 28.
    Casagrande, V., Menghini, R., Menini, S., Marino, A., Marchetti, V., Cavalera, M., et al. (2012). Overexpression of tissue inhibitor of metalloproteinase 3 in macrophages reduces atherosclerosis in low-density lipoprotein receptor knockout mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 32, 74–81.PubMedCrossRefGoogle Scholar
  29. 29.
    Menghini, R., Casagrande, V., Menini, S., Marino, A., Marzano, V., Hribal, M. L., et al. (2012). TIMP3 overexpression in macrophages protects from insulin resistance, adipose inflammation, and nonalcoholic fatty liver disease in mice. Diabetes, 61, 454–462.PubMedCrossRefGoogle Scholar
  30. 30.
    Fiorentino, L., Cavalera, M., Menini, S., Marchetti, V., Mavilio, M., Fabrizi, M., et al. (2013). Loss of TIMP3 underlies diabetic nephropathy via FoxO1/STAT1 interplay. EMBO Molecular Medicine, 5, 441–455.PubMedCrossRefGoogle Scholar
  31. 31.
    Cardellini, M., Menghini, R., Martelli, E., Casagrande, V., Marino, A., Rizza, S., et al. (2009). TIMP3 is reduced in atherosclerotic plaques from subjects with type 2 diabetes and increased by SirT1. Diabetes, 58, 2396–2401.PubMedCrossRefGoogle Scholar
  32. 32.
    Greco, S., Fasanaro, P., Castelvecchio, S., D’Alessandra, Y., Arcelli, D., Di Donato, M., et al. (2012). MicroRNA dysregulation in diabetic ischemic heart failure patients. Diabetes, 61, 1633–1641.PubMedCrossRefGoogle Scholar
  33. 33.
    Wang, S., Aurora, A. B., Johnson, B. A., Qi, X., McAnally, J., Hill, J. A., et al. (2008). The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Developmental Cell, 15, 261–271.PubMedCrossRefGoogle Scholar
  34. 34.
    Harris, T. A., Yamakuchi, M., Ferlito, M., Mendell, J. T., & Lowenstein, C. J. (2008). MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proceedings of the National Academy of Sciences of the United States of America, 105, 1516–1521.PubMedCrossRefGoogle Scholar
  35. 35.
    Bonauer, A., Carmona, G., Iwasaki, M., Mione, M., Koyanagi, M., Fischer, A., et al. (2009). MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science, 324, 1710–1713.PubMedCrossRefGoogle Scholar
  36. 36.
    Fang, Y., & Davies, P. F. (2012). Site-specific microRNA-92a regulation of Kruppel-like factors 4 and 2 in atherosusceptible endothelium. Arteriosclerosis, Thrombosis, and Vascular Biology, 32, 979–987.PubMedCrossRefGoogle Scholar
  37. 37.
    Sabatel, C., Malvaux, L., Bovy, N., Deroanne, C., Lambert, V., Gonzalez, M. L., et al. (2011). MicroRNA-21 exhibits antiangiogenic function by targeting RhoB expression in endothelial cells. PLoS One, 6, e16979.PubMedCrossRefGoogle Scholar
  38. 38.
    Zhou, J., Wang, W. W., Subramaniam, S., Shyy, J. Y., Chiu, J. J., Li, J. Y., et al. (2011). MicroRNA-21 targets peroxisome proliferators-activated receptor-α in an autoregulatory loop to modulate flow-induced endothelial inflammation. Proceedings of the National Academy of Sciences of the United States of America, 108, 10355–10360.PubMedCrossRefGoogle Scholar
  39. 39.
    Chen, L. J., Lim, S. H., Yeh, Y. T., Lien, S. C., & Chiu, J. J. (2012). Roles of microRNAs in atherosclerosis and restenosis. Journal of Biomedical Science, 19, 79.PubMedCrossRefGoogle Scholar
  40. 40.
    Raitoharju, E., Lyytikäinen, L. P., Levula, M., Oksala, N., Mennander, A., Tarkka, M., et al. (2011). MiR-21, miR-210, miR-34a, and miR-146a/b are up-regulated in human atherosclerotic plaques in the Tampere Vascular Study. Atherosclerosis, 219, 211–217.PubMedCrossRefGoogle Scholar
  41. 41.
    Li, T., Cao, H., Zhuang, J., Wan, J., Guan, M., Yu, B., et al. (2011). Identification of miR-130a, miR-27b and miR-210 as serum biomarkers for atherosclerosis obliterans. Clinica Chimica Acta, 412, 66–70.CrossRefGoogle Scholar
  42. 42.
    Takahashi, Y., Satoh, M., Minami, Y., Tabuchi, T., Itoh, T., & Nakamura, M. (2010). Expression of miR-146a/b is associated with the Toll-like receptor 4 signal in coronary artery disease: effect of renin-angiotensin system blockade and statins on miRNA-146a/b and Toll-like receptor 4 levels. Clinical Science (London, England), 119, 395–405.CrossRefGoogle Scholar
  43. 43.
    Guo, M., Mao, X., Ji, Q., Lang, M., Li, S., Peng, Y., et al. (2010). MiR-146a in PBMCs modulates Th1 function in patients with acute coronary syndrome. Immunology and Cell Biology, 88, 555–564.PubMedCrossRefGoogle Scholar
  44. 44.
    Du, F., Zhou, J., Gong, R., Huang, X., Pansuria, M., Virtue, A., et al. (2012). Endothelial progenitor cells in atherosclerosis. Frontiers in Bioscience, 17, 2327–2349.CrossRefGoogle Scholar
  45. 45.
    Zhang, Q., Kandic, I., & Kutryk, M. J. (2011). Dysregulation of angiogenesis-related microRNAs in endothelial progenitor cells from patients with coronary artery disease. Biochemical and Biophysical Research Communications, 405, 42–46.PubMedCrossRefGoogle Scholar
  46. 46.
    Zhao, T., Li, J., & Chen, A. F. (2010). MicroRNA-34a induces endothelial progenitor cell senescence and impedes its angiogenesis via suppressing silent information regulator 1. American Journal of Physiology, Endocrinology and Metabolism, 299, E110–E116.CrossRefGoogle Scholar
  47. 47.
    Zernecke, A., Bidzhekov, K., Noels, H., Shagdarsuren, E., Gan, L., Denecke, B., et al. (2009). Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Science Signaling, 2, ra81.PubMedCrossRefGoogle Scholar
  48. 48.
    Hunter, M. P., Ismail, N., Zhang, X., Aguda, B. D., Lee, E. J., Yu, L., et al. (2008). Detection of microRNA expression in human peripheral blood microvesicles. PLoS One, 3, e3694.PubMedCrossRefGoogle Scholar
  49. 49.
    Zampetaki, A., Kiechl, S., Drozdov, I., Willeit, P., Mayr, U., Prokopi, M., et al. (2010). Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circulation Research, 107, 810–817.PubMedCrossRefGoogle Scholar
  50. 50.
    Fichtlscherer, S., De Rosa, S., Fox, H., Schwietz, T., Fischer, A., Liebetrau, C., et al. (2010). Circulating microRNAs in patients with coronary artery disease. Circulation Research, 107, 677–684.PubMedCrossRefGoogle Scholar
  51. 51.
    Yao, R., Ma, Y., Du, Y., Liao, M., Li, H., Liang, W., et al. (2011). The altered expression of inflammation-related microRNAs with microRNA-155 expression correlates with Th17 differentiation in patients with acute coronary syndrome. Cellular and molecular immunology, 8, 486–495.PubMedCrossRefGoogle Scholar
  52. 52.
    Wang, H., Lu, H. M., Yang, W. H., Luo, C., Lu, S. H., Zhou, Y., et al. (2012). The influence of statin therapy on circulating microRNA-92a expression in patients with coronary heart disease. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue, 24, 215–218.PubMedGoogle Scholar
  53. 53.
    Nazari-Jahantigh, M., Wei, Y., Noels, H., Akhtar, S., Zhou, Z., Koenen, R. R., et al. (2012). MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages. The Journal of Clinical Investigation, 122, 4190–4202.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Rossella Menghini
    • 1
  • Viviana Casagrande
    • 1
  • Massimo Federici
    • 1
    • 2
  1. 1.Department of Systems MedicineUniversity of Rome “Tor Vergata”RomeItaly
  2. 2.Center for AtherosclerosisTor Vergata University Hospital “Policlinico Tor Vergata”RomeItaly

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