Skip to main content

Advertisement

SpringerLink
Log in

Endothelial MicroRNAs and Atherosclerosis

  • Clinical Trials and Their Interpretations (J Plutzky, Section Editor)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

The vascular endothelium, a thin layer of endothelial cells (ECs) that line the inner surface of blood vessels, is a critical interface between blood and all tissues. EC activation, dysfunction, and vascular inflammation occur when the endothelium is exposed to various insults such as proinflammatory cytokines, oxidative stress, hypertension, hyperglycemia, aging, and shear stress. These insults lead to the pathogenesis of a range of disease states, including atherosclerosis. Several signaling pathways, especially nuclear factor κB mediated signaling, play crucial roles in these pathophysiological processes. Recently, microRNAs (miRNAs) have emerged as important regulators of EC function by fine-tuning gene expression. In this review, we discuss how miRNAs regulate EC function and vascular inflammation in response to a variety of pathophysiologic stimuli. An understanding of the role of miRNAs in EC activation and dysfunction may provide novel targets and therapeutic opportunities for controlling atherosclerosis and other chronic inflammatory disease states.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. •• Libby P, Ridker PM, Hansson GK. Progress and challenges in translating the biology of atherosclerosis. Nature. 2011;473(7347):317–25. This review article summarized the current understanding of atherosclerosis, and highlighted the gap between experimental animal findings and clinical applications.

    PubMed  CAS  Google Scholar 

  2. Libby P. Inflammation in atherosclerosis. Nature. 2002;420(6917):868–74.

    PubMed  CAS  Google Scholar 

  3. Tabas I, Williams KJ, Boren J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 2007;116(16):1832–44.

    PubMed  CAS  Google Scholar 

  4. Rayner KJ, Moore KJ. The plaque "micro" environment: microRNAs control the risk and the development of atherosclerosis. Curr Atheroscler Rep. 2012;14(5):413–21.

    PubMed  CAS  Google Scholar 

  5. Madrigal-Matute J, Rotllan N, Aranda JF, Fernandez-Hernando C. MicroRNAs and atherosclerosis. Curr Atheroscler Rep. 2013;15(5):322.

    PubMed  Google Scholar 

  6. • Wei Y, Nazari-Jahantigh M, Neth P, Weber C, Schober A. MicroRNA-126, -145, and -155: a therapeutic triad in atherosclerosis? Arterioscler Thromb Vasc Biol. 2013;33(3):449–54. This review discussed the role of EC miR-126, SMC miR-145, and macrophage miR-155 in the pathogenesis of atherosclerosis.

    PubMed  CAS  Google Scholar 

  7. Shan Z, Yao C, Li ZL, et al. Differentially expressed microRNAs at different stages of atherosclerosis in ApoE-deficient mice. Chin Med J. 2013;126(3):515–20.

    PubMed  CAS  Google Scholar 

  8. Wei Y, Nazari-Jahantigh M, Chan L, et al. The microRNA-342-5p fosters inflammatory macrophage activation through an Akt1- and microRNA-155-dependent pathway during atherosclerosis. Circulation. 2013;127(15):1609–19.

    PubMed  CAS  Google Scholar 

  9. Rayner KJ, Fernandez-Hernando C, Moore KJ. MicroRNAs regulating lipid metabolism in atherogenesis. Thromb Haemost. 2012;107(4):642–7.

    PubMed  CAS  Google Scholar 

  10. Rotllan N, Fernandez-Hernando C. MicroRNA regulation of cholesterol metabolism. Cholesterol. 2012;2012:847849.

    PubMed  Google Scholar 

  11. Neth P, Nazari-Jahantigh M, Schober A, Weber C. MicroRNAs in flow-dependent vascular remodelling. Cardiovasc Res. 2013;99(2):294–303.

    PubMed  CAS  Google Scholar 

  12. Boon RA, Hergenreider E, Dimmeler S. Atheroprotective mechanisms of shear stress-regulated microRNAs. Thromb Haemost. 2012;108(4):616–20.

    PubMed  CAS  Google Scholar 

  13. Chamorro-Jorganes A, Araldi E, Suarez Y. MicroRNAs as pharmacological targets in endothelial cell function and dysfunction. Pharmacol Res. 2013;75:15–27.

    PubMed  CAS  Google Scholar 

  14. Nakashima Y, Plump AS, Raines EW, Breslow JL, Ross R. ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler Thromb. 1994;14(1):133–40.

    PubMed  CAS  Google Scholar 

  15. • Baker RG, Hayden MS, Ghosh S. NF-κB, inflammation, and metabolic disease. Cell Metab. 2011;13(1):11–22. This review examined the role of the NF-κB pathway in the development of inflammation-associated metabolic diseases, including obesity, diabetes, and atherosclerosis.

    PubMed  CAS  Google Scholar 

  16. Weisberg SP, Hunter D, Huber R, et al. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest. 2006;116(1):115–24.

    PubMed  CAS  Google Scholar 

  17. Hernández-Presa M, Bustos C, Ortego M, et al. Angiotensin-converting enzyme inhibition prevents arterial nuclear factor-kappa B activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis. Circulation. 1997;95(6):1532–41.

    PubMed  Google Scholar 

  18. Palinski W, Ord VA, Plump AS, Breslow JL, Steinberg D, Witztum JL. ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum. Arterioscler Thromb. 1994;14(4):605–16.

    PubMed  CAS  Google Scholar 

  19. Hajra L, Evans AI, Chen M, Hyduk SJ, Collins T, Cybulsky MI. The NF-κB signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation. Proc Natl Acad Sci U S A. 2000;97(16):9052–7.

    PubMed  CAS  Google Scholar 

  20. Davies PF, Polacek DC, Handen JS, Helmke BP, DePaola N. A spatial approach to transcriptional profiling: mechanotransduction and the focal origin of atherosclerosis. Trends Biotechnol. 1999;17(9):347–51.

    PubMed  CAS  Google Scholar 

  21. Kannel WB, McGee DL. Diabetes and cardiovascular risk factors: the Framingham study. Circulation. 1979;59(1):8–13.

    PubMed  CAS  Google Scholar 

  22. Hayden MS, Ghosh S. Shared principles in NF-κB signaling. Cell. 2008;132(3):344–62.

    PubMed  CAS  Google Scholar 

  23. Jayawardena TM, Egemnazarov B, Finch EA, et al. MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes. Circ Res. 2012;110(11):1465–73.

    PubMed  CAS  Google Scholar 

  24. Karin M, Ben-Neriah Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu Rev Immunol. 2000;18:621–63.

    PubMed  CAS  Google Scholar 

  25. Ghosh S, Hayden MS. New regulators of NF-κB in inflammation. Nat Rev Immunol. 2008;8(11):837–48.

    PubMed  CAS  Google Scholar 

  26. Oeckinghaus A, Ghosh S. The NF-κB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol. 2009;1(4):a000034.

    PubMed  Google Scholar 

  27. Sen R, Smale ST. Selectivity of the NF-κB response. Cold Spring Harb Perspect Biol. 2010;2(4):a000257.

    PubMed  Google Scholar 

  28. Smale ST. Selective transcription in response to an inflammatory stimulus. Cell. 2010;140(6):833–44.

    PubMed  CAS  Google Scholar 

  29. Vallabhapurapu S, Karin M. Regulation and function of NF-κB transcription factors in the immune system. Annu Rev Immunol. 2009;27:693–733.

    PubMed  CAS  Google Scholar 

  30. • Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32(9):2045–51. This review discussed the role of inflammation in aspects of experimental atherosclerosis, and the implications for the translation of these concepts to clinical practice.

    PubMed  CAS  Google Scholar 

  31. Brand K, Page S, Rogler G, et al. Activated transcription factor nuclear factor-kappa B is present in the atherosclerotic lesion. J Clin Invest. 1996;97(7):1715–22.

    PubMed  CAS  Google Scholar 

  32. Wilson SH, Caplice NM, Simari RD, Holmes Jr DR, Carlson PJ, Lerman A. Activated nuclear factor-κB is present in the coronary vasculature in experimental hypercholesterolemia. Atherosclerosis. 2000;148(1):23–30.

    PubMed  CAS  Google Scholar 

  33. Gareus R, Kotsaki E, Xanthoulea S, et al. Endothelial cell-specific NF-κB inhibition protects mice from atherosclerosis. Cell Metab. 2008;8(5):372–83.

    PubMed  CAS  Google Scholar 

  34. Bourdillon MC, Poston RN, Covacho C, Chignier E, Bricca G, McGregor JL. ICAM-1 deficiency reduces atherosclerotic lesions in double-knockout mice (ApoE-/-/ICAM-1-/-) fed a fat or a chow diet. Arterioscler Thromb Vasc Biol. 2000;20(12):2630–5.

    PubMed  CAS  Google Scholar 

  35. Dong ZM, Chapman SM, Brown AA, Frenette PS, Hynes RO, Wagner DD. The combined role of P- and E-selectins in atherosclerosis. J Clin Invest. 1998;102(1):145–52.

    PubMed  CAS  Google Scholar 

  36. Cybulsky MI, Iiyama K, Li H, et al. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest. 2001;107(10):1255–62.

    PubMed  CAS  Google Scholar 

  37. Polykratis A, van Loo G, Xanthoulea S, Hellmich M, Pasparakis M. Conditional targeting of tumor necrosis factor receptor-associated factor 6 reveals opposing functions of Toll-like receptor signaling in endothelial and myeloid cells in a mouse model of atherosclerosis. Circulation. 2012;126(14):1739–51.

    PubMed  CAS  Google Scholar 

  38. Park SH, Sui Y, Gizard F, et al. Myeloid-specific IκB kinase beta deficiency decreases atherosclerosis in low-density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2012;32(12):2869–76.

    PubMed  CAS  Google Scholar 

  39. Kanters E, Pasparakis M, Gijbels MJ, et al. Inhibition of NF-κB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2003;112(8):1176–85.

    PubMed  CAS  Google Scholar 

  40. Harris TA, Yamakuchi M, Ferlito M, Mendell JT, Lowenstein CJ. MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci U S A. 2008;105(5):1516–21.

    PubMed  CAS  Google Scholar 

  41. Sun C, Alkhoury K, Wang YI, et al. IRF-1 and miRNA126 modulate VCAM-1 expression in response to a high-fat meal. Circ Res. 2012;111(8):1054–64.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  43. Oettgen P. Regulation of vascular inflammation and remodeling by ETS factors. Circ Res. 2006;99(11):1159–66.

    PubMed  CAS  Google Scholar 

  44. Harris TA, Yamakuchi M, Kondo M, Oettgen P, Lowenstein CJ. Ets-1 and Ets-2 regulate the expression of microRNA-126 in endothelial cells. Arterioscler Thromb Vasc Biol. 2010;30(10):1990–7.

    PubMed  CAS  Google Scholar 

  45. Zhan Y, Brown C, Maynard E, et al. Ets-1 is a critical regulator of Ang II-mediated vascular inflammation and remodeling. J Clin Invest. 2005;115(9):2508–16.

    PubMed  CAS  Google Scholar 

  46. Zernecke A, Bidzhekov K, Noels H, et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal. 2009;2(100):ra81.

    PubMed  Google Scholar 

  47. Fichtlscherer S, De Rosa S, Fox H, et al. Circulating microRNAs in patients with coronary artery disease. Circ Res. 2010;107(5):677–84.

    PubMed  CAS  Google Scholar 

  48. Tan KS, Armugam A, Sepramaniam S, et al. Expression profile of microRNAs in young stroke patients. PLoS One. 2009;4(11):e7689.

    PubMed  Google Scholar 

  49. •• Sun X, Icli B, Wara AK, et al. MicroRNA-181b regulates NF-κB-mediated vascular inflammation. J Clin Invest. 2012;122(6):1973–90. This study identified miR-181b as a critical negative regulator of NF-κB downstream signaling by targeting the 3′ UTR of importin-α3, which is a protein involved in NF-κB nuclear translocation. With use of a mouse model of endotoxemia, the authors provided proof-of-concept evidence that miRNA mimics can be used to target the vascular endothelium, and inhibit the deleterious effect of NF-κB signaling in acute inflammatory states in vivo.

    PubMed  CAS  Google Scholar 

  50. Theiss AL, Jenkins AK, Okoro NI, Klapproth JM, Merlin D, Sitaraman SV. Prohibitin inhibits tumor necrosis factor alpha-induced nuclear factor-kappa B nuclear translocation via the novel mechanism of decreasing importin α3 expression. Mol Biol Cell. 2009;20(20):4412–23.

    PubMed  CAS  Google Scholar 

  51. Kohler M, Speck C, Christiansen M, et al. Evidence for distinct substrate specificities of importin alpha family members in nuclear protein import. Mol Cell Biol. 1999;19(11):7782–91.

    PubMed  CAS  Google Scholar 

  52. Fagerlund R, Melen K, Cao X, Julkunen I. NF-κB p52, RelB and c-Rel are transported into the nucleus via a subset of importin alpha molecules. Cell Signal. 2008;20(8):1442–51.

    PubMed  CAS  Google Scholar 

  53. Fagerlund R, Kinnunen L, Kohler M, Julkunen I, Melen K. NF-κB is transported into the nucleus by importin α3 and importin α4. J Biol Chem. 2005;280(16):15942–51.

    PubMed  CAS  Google Scholar 

  54. •• Sun X, He S, Wara AK, et al. Systemic delivery of microRNA-181b inhibits NF-kB activation, vascular inflammation, and atherosclerosis in ApoE-/- mice. Circ Res. 2013. doi:10.1161/CIRCRESAHA.113.302089. This article demonstrated that miR-181b mimics can be delivered to the vascular endothelium in chronic inflammatory disease states such as atherosclerosis; miR-181b inhibited NF-κB activation specifically in ECs, but not leukocytes, an effect sufficient to inhibit atherogenesis in ApoE -/- mice.

    Google Scholar 

  55. Tergaonkar V, Perkins ND. p53 and NF-κB crosstalk: IKKα tips the balance. Mol Cell. 2007;26(2):158–9.

    PubMed  CAS  Google Scholar 

  56. Perkins ND. Integrating cell-signalling pathways with NF-κB and IKK function. Nat Rev Mol Cell Biol. 2007;8(1):49–62.

    PubMed  CAS  Google Scholar 

  57. Oeckinghaus A, Hayden MS, Ghosh S. Crosstalk in NF-κB signaling pathways. Nat Immunol. 2011;12(8):695–708.

    PubMed  CAS  Google Scholar 

  58. Ashida N, Senbanerjee S, Kodama S, et al. IKKβ regulates essential functions of the vascular endothelium through kinase-dependent and -independent pathways. Nat Commun. 2011;2:318.

    PubMed  Google Scholar 

  59. • Suarez Y, Wang C, Manes TD, Pober JS. Cutting edge: TNF-induced microRNAs regulate TNF-induced expression of E-selectin and intercellular adhesion molecule-1 on human endothelial cells: feedback control of inflammation. J Immunol. 2010;184(1):21–5. In this study, a negative-feedback loop was identified in which miR-31 expression and miR-17-3p expression were induced by TNF-α in ECs to inhibit EC activation by reducing the expression of adhesion molecules.

    PubMed  CAS  Google Scholar 

  60. •• Cheng HS, Sivachandran N, Lau A, et al. MicroRNA-146 represses endothelial activation by inhibiting pro-inflammatory pathways. EMBO Mol Med. 2013;5(7):1017–34. This article elegantly dissected the inhibitory role of miR-146 in EC activation and provides further support for developing miRNA-based therapies targeting vascular ECs.

    Google Scholar 

  61. Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. JAMA. 1979;241(19):2035–8.

    PubMed  CAS  Google Scholar 

  62. Howard G, O'Leary DH, Zaccaro D, et al. Insulin sensitivity and atherosclerosis. The Insulin Resistance Atherosclerosis Study (IRAS) Investigators. Circulation. 1996;93(10):1809–17.

    PubMed  CAS  Google Scholar 

  63. Guerci B, Bohme P, Kearney-Schwartz A, Zannad F, Drouin P. Endothelial dysfunction and type 2 diabetes. Part 2: altered endothelial function and the effects of treatments in type 2 diabetes mellitus. Diabetes Metab. 2001;27(4 Pt 1):436–47.

    PubMed  CAS  Google Scholar 

  64. Hasegawa Y, Saito T, Ogihara T, et al. Blockade of the nuclear factor-κB pathway in the endothelium prevents insulin resistance and prolongs life spans. Circulation. 2012;125(9):1122–33.

    PubMed  CAS  Google Scholar 

  65. Wang XH, Qian RZ, Zhang W, Chen SF, Jin HM, Hu RM. MicroRNA-320 expression in myocardial microvascular endothelial cells and its relationship with insulin-like growth factor-1 in type 2 diabetic rats. Clin Exp Pharmacol Physiol. 2009;36(2):181–8.

    PubMed  Google Scholar 

  66. Caporali A, Meloni M, Vollenkle C, et al. Deregulation of microRNA-503 contributes to diabetes mellitus-induced impairment of endothelial function and reparative angiogenesis after limb ischemia. Circulation. 2011;123(3):282–91.

    PubMed  CAS  Google Scholar 

  67. Long J, Wang Y, Wang W, Chang BH, Danesh FR. MicroRNA-29c is a signature microRNA under high glucose conditions that targets Sprouty homolog 1, and its in vivo knockdown prevents progression of diabetic nephropathy. J Biol Chem. 2011;286(13):11837–48.

    PubMed  CAS  Google Scholar 

  68. Li Y, Song YH, Li F, Yang T, Lu YW, Geng YJ. MicroRNA-221 regulates high glucose-induced endothelial dysfunction. Biochem Biophys Res Commun. 2009;381(1):81–3.

    PubMed  CAS  Google Scholar 

  69. Togliatto G, Trombetta A, Dentelli P, Rosso A, Brizzi MF. MIR221/MIR222-driven post-transcriptional regulation of P27KIP1 and P57KIP2 is crucial for high-glucose- and AGE-mediated vascular cell damage. Diabetologia. 2011;54(7):1930–40.

    PubMed  CAS  Google Scholar 

  70. Vasa-Nicotera M, Chen H, Tucci P, et al. miR-146a is modulated in human endothelial cell with aging. Atherosclerosis. 2011;217(2):326–30.

    PubMed  CAS  Google Scholar 

  71. Ito T, Yagi S, Yamakuchi M. MicroRNA-34a regulation of endothelial senescence. Biochem Biophys Res Commun. 2010;398(4):735–40.

    PubMed  CAS  Google Scholar 

  72. Tazawa H, Tsuchiya N, Izumiya M, Nakagama H. Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells. Proc Natl Acad Sci U S A. 2007;104(39):15472–7.

    PubMed  CAS  Google Scholar 

  73. Menghini R, Casagrande V, Cardellini M, et al. MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1. Circulation. 2009;120(15):1524–32.

    PubMed  CAS  Google Scholar 

  74. Haigis MC, Guarente LP. Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction. Genes Dev. 2006;20(21):2913–21.

    PubMed  CAS  Google Scholar 

  75. Raitoharju E, Lyytikainen LP, Levula M, et al. miR-21, miR-210, miR-34a, and miR-146a/b are up-regulated in human atherosclerotic plaques in the Tampere Vascular Study. Atherosclerosis. 2011;219(1):211–7.

    PubMed  CAS  Google Scholar 

  76. Boon RA, Iekushi K, Lechner S, et al. MicroRNA-34a regulates cardiac ageing and function. Nature. 2013;495(7439):107–10.

    PubMed  CAS  Google Scholar 

  77. Li D, Yang P, Xiong Q, et al. MicroRNA-125a/b-5p inhibits endothelin-1 expression in vascular endothelial cells. J Hypertens. 2010;28(8):1646–54.

    PubMed  CAS  Google Scholar 

  78. Zhang XY, Shen BR, Zhang YC, et al. Induction of thoracic aortic remodeling by endothelial-specific deletion of microRNA-21 in mice. PLoS One. 2013;8(3):e59002.

    PubMed  CAS  Google Scholar 

  79. Zhu N, Zhang D, Chen S, et al. Endothelial enriched microRNAs regulate angiotensin II-induced endothelial inflammation and migration. Atherosclerosis. 2011;215(2):286–93.

    PubMed  CAS  Google Scholar 

  80. Zheng L, Xu CC, Chen WD, et al. MicroRNA-155 regulates angiotensin II type 1 receptor expression and phenotypic differentiation in vascular adventitial fibroblasts. Biochem Biophys Res Commun. 2010;400(4):483–8.

    PubMed  CAS  Google Scholar 

  81. Cheng W, Liu T, Jiang F, et al. MicroRNA-155 regulates angiotensin II type 1 receptor expression in umbilical vein endothelial cells from severely pre-eclamptic pregnant women. Int J Mol Med. 2011;27(3):393–9.

    PubMed  CAS  Google Scholar 

  82. Liu T, Shen D, Xing S, et al. Attenuation of exogenous angiotensin II stress-induced damage and apoptosis in human vascular endothelial cells via microRNA-155 expression. Int J Mol Med. 2013;31(1):188–96.

    PubMed  CAS  Google Scholar 

  83. Pulkkinen KH, Yla-Herttuala S, Levonen AL. Heme oxygenase 1 is induced by miR-155 via reduced BACH1 translation in endothelial cells. Free Radic Biol Med. 2011;51(11):2124–31.

    PubMed  CAS  Google Scholar 

  84. Sun HX, Zeng DY, Li RT, et al. Essential role of microRNA-155 in regulating endothelium-dependent vasorelaxation by targeting endothelial nitric oxide synthase. Hypertension. 2012;60(6):1407–14.

    PubMed  CAS  Google Scholar 

  85. Donners MM, Wolfs IM, Stoger LJ, et al. Hematopoietic miR155 deficiency enhances atherosclerosis and decreases plaque stability in hyperlipidemic mice. PLoS One. 2012;7(4):e35877.

    PubMed  CAS  Google Scholar 

  86. Nazari-Jahantigh M, Wei Y, Noels H, et al. MicroRNA-155 promotes atherosclerosis by repressing Bcl6 in macrophages. J Clin Invest. 2012;122(11):4190–202.

    PubMed  CAS  Google Scholar 

  87. Zhu J, Chen T, Yang L, et al. Regulation of microRNA-155 in atherosclerotic inflammatory responses by targeting MAP3K10. PLoS One. 2012;7(11):e46551.

    PubMed  CAS  Google Scholar 

  88. Frangos SG, Gahtan V, Sumpio B. Localization of atherosclerosis: role of hemodynamics. Arch Surg. 1999;134(10):1142–9.

    PubMed  CAS  Google Scholar 

  89. Chiu JJ, Chien S. Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives. Physiol Rev. 2011;91(1):327–87.

    PubMed  Google Scholar 

  90. DePaola N, Davies PF, Pritchard Jr WF, Florez L, Harbeck N, Polacek DC. Spatial and temporal regulation of gap junction connexin43 in vascular endothelial cells exposed to controlled disturbed flows in vitro. Proc Natl Acad Sci U S A. 1999;96(6):3154–9.

    PubMed  CAS  Google Scholar 

  91. Miao H, Hu YL, Shiu YT, et al. Effects of flow patterns on the localization and expression of VE-cadherin at vascular endothelial cell junctions: in vivo and in vitro investigations. J Vasc Res. 2005;42(1):77–89.

    PubMed  CAS  Google Scholar 

  92. Chiu JJ, Chen CN, Lee PL, et al. Analysis of the effect of disturbed flow on monocytic adhesion to endothelial cells. J Biomech. 2003;36(12):1883–95.

    PubMed  Google Scholar 

  93. Chiu JJ, Chen LJ, Lee PL, et al. Shear stress inhibits adhesion molecule expression in vascular endothelial cells induced by coculture with smooth muscle cells. Blood. 2003;101(7):2667–74.

    PubMed  CAS  Google Scholar 

  94. Yamawaki H, Pan S, Lee RT, Berk BC. Fluid shear stress inhibits vascular inflammation by decreasing thioredoxin-interacting protein in endothelial cells. J Clin Invest. 2005;115(3):733–8.

    PubMed  CAS  Google Scholar 

  95. Tardy Y, Resnick N, Nagel T, Gimbrone Jr MA, Dewey Jr CF. Shear stress gradients remodel endothelial monolayers in vitro via a cell proliferation-migration-loss cycle. Arterioscler Thromb Vasc Biol. 1997;17(11):3102–6.

    PubMed  CAS  Google Scholar 

  96. Chien S. Molecular and mechanical bases of focal lipid accumulation in arterial wall. Prog Biophys Mol Biol. 2003;83(2):131–51.

    PubMed  CAS  Google Scholar 

  97. Qin X, Wang X, Wang Y, et al. MicroRNA-19a mediates the suppressive effect of laminar flow on cyclin D1 expression in human umbilical vein endothelial cells. Proc Natl Acad Sci U S A. 2010;107(7):3240–4.

    PubMed  CAS  Google Scholar 

  98. Wang KC, Garmire LX, Young A, et al. Role of microRNA-23b in flow-regulation of Rb phosphorylation and endothelial cell growth. Proc Natl Acad Sci U S A. 2010;107(7):3234–9.

    PubMed  CAS  Google Scholar 

  99. Zhu S, Pan W, Song X, et al. The microRNA miR-23b suppresses IL-17-associated autoimmune inflammation by targeting TAB2, TAB3 and IKK-α. Nat Med. 2012;18:1077–86.

    PubMed  CAS  Google Scholar 

  100. Urbich C, Kaluza D, Fromel T, et al. MicroRNA-27a/b controls endothelial cell repulsion and angiogenesis by targeting semaphorin 6A. Blood. 2012;119(6):1607–16.

    PubMed  CAS  Google Scholar 

  101. Chen K, Fan W, Wang X, Ke X, Wu G, Hu C. MicroRNA-101 mediates the suppressive effect of laminar shear stress on mTOR expression in vascular endothelial cells. Biochem Biophys Res Commun. 2012;427(1):138–42.

    PubMed  CAS  Google Scholar 

  102. •• Fang Y, Shi C, Manduchi E, Civelek M, Davies PF. MicroRNA-10a regulation of proinflammatory phenotype in athero-susceptible endothelium in vivo and in vitro. Proc Natl Acad Sci U S A. 2010;107(30):13450–5. This study first identified miRNAs differentially expressed between the atherosusceptible and the atheroresistant regions in vivo in swine aortic artery, and found endothelial miR-10a expression is lower in the atherosusceptible regions. The study suggests the lower miR-10a expression may contribute to the proinflammatory endothelial phenotypes in atherosusceptible regions.

    PubMed  CAS  Google Scholar 

  103. Zhou J, Wang KC, Wu W, et al. MicroRNA-21 targets peroxisome proliferators-activated receptor-α in an autoregulatory loop to modulate flow-induced endothelial inflammation. Proc Natl Acad Sci U S A. 2011;108(25):10355–60.

    PubMed  CAS  Google Scholar 

  104. Ni CW, Qiu H, Jo H. MicroRNA-663 upregulated by oscillatory shear stress plays a role in inflammatory response of endothelial cells. Am J Physiol Heart Circ Physiol. 2011;300(5):H1762–9.

    PubMed  CAS  Google Scholar 

  105. •• Wu W, Xiao H, Laguna-Fernandez A, et al. Flow-dependent regulation of Krüppel-like factor 2 is mediated by microRNA-92a. Circulation. 2011;124(5):633–41. This study highlights that miR-92a expression is reduced by atheroprotective flow patterns, which resulted in the upregulation of KLF2. Overexpression of miR-92a in mouse carotid arteries exhibited impaired flow-mediated vasodilatory response.

    PubMed  CAS  Google Scholar 

  106. Fang Y, Davies PF. Site-specific microRNA-92a regulation of Krüppel-like factors 4 and 2 in atherosusceptible endothelium. Arterioscler Thromb Vasc Biol. 2012;32(4):979–87.

    PubMed  CAS  Google Scholar 

  107. Zhou J, Li JY, Nguyen P, et al. Regulation of vascular smooth muscle cell turnover by endothelial cell-secreted microRNA-126: role of shear stress. Circ Res. 2013;113:40–51.

    PubMed  CAS  Google Scholar 

  108. Hergenreider E, Heydt S, Treguer K, et al. Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nat Cell Biol. 2012;14(3):249–56.

    PubMed  CAS  Google Scholar 

  109. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105(9):1135–43.

    PubMed  CAS  Google Scholar 

  110. Martinez NJ, Gregory RI. MicroRNA gene regulatory pathways in the establishment and maintenance of ESC identity. Cell Stem Cell. 2010;7(1):31–5.

    PubMed  CAS  Google Scholar 

  111. Marson A, Levine SS, Cole MF, et al. Connecting microRNA genes to the core transcriptional regulatory circuitry of embryonic stem cells. Cell. 2008;134(3):521–33.

    PubMed  CAS  Google Scholar 

  112. Wang Y, Baskerville S, Shenoy A, Babiarz JE, Baehner L, Blelloch R. Embryonic stem cell-specific microRNAs regulate the G1-S transition and promote rapid proliferation. Nat Genet. 2008;40(12):1478–83.

    PubMed  CAS  Google Scholar 

  113. Card DAG, Hebbar PB, Li L, et al. Oct4/Sox2-regulated miR-302 targets cyclin D1 in human embryonic stem cells. Mol Cell Biol. 2008;28(20):6426–38.

    PubMed  Google Scholar 

  114. Judson RL, Babiarz JE, Venere M, Blelloch R. Embryonic stem cell-specific microRNAs promote induced pluripotency. Nat Biotechnol. 2009;27(5):459–61.

    PubMed  CAS  Google Scholar 

  115. Melton C, Judson RL, Blelloch R. Opposing microRNA families regulate self-renewal in mouse embryonic stem cells. Nature. 2010;463(7281):621–6.

    PubMed  CAS  Google Scholar 

  116. Anokye-Danso F, Trivedi CM, Juhr D, et al. Highly efficient miRNA-mediated reprogramming of mouse and human somatic cells to pluripotency. Cell Stem Cell. 2011;8(4):376–88.

    PubMed  CAS  Google Scholar 

  117. Yang WJ, Yang DD, Na S, Sandusky GE, Zhang Q, Zhao G. Dicer is required for embryonic angiogenesis during mouse development. J Biol Chem. 2005;280(10):9330–5.

    PubMed  CAS  Google Scholar 

  118. Suárez Y, Fernández-Hernando C, Yu J, et al. Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis. Proc Natl Acad Sci U S A. 2008;105(37):14082–7.

    PubMed  Google Scholar 

  119. Kuehbacher A, Urbich C, Zeiher AM, Dimmeler S. Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis. Circ Res. 2007;101(1):59–68.

    PubMed  CAS  Google Scholar 

  120. Kane NM, Meloni M, Spencer HL, et al. Derivation of endothelial cells from human embryonic stem cells by directed differentiation analysis of microRNA and angiogenesis in vitro and in vivo. Arterioscler Thromb Vasc Biol. 2010;30(7):1389–97.

    PubMed  CAS  Google Scholar 

  121. Tréguer K, Heinrich E-M, Ohtani K, Bonauer A, Dimmeler S. Role of the microRNA-17–92 cluster in the endothelial differentiation of stem cells. J Vasc Res. 2012;49(5):447–60.

    PubMed  Google Scholar 

  122. Kane NM, Howard L, Descamps B, et al. Role of microRNAs 99b, 181a, and 181b in the differentiation of human embryonic stem cells to vascular endothelial cells. Stem Cells. 2012;30(4):643–54.

    PubMed  CAS  Google Scholar 

  123. Kazenwadel J, Michael MZ, Harvey NL. Prox1 expression is negatively regulated by miR-181 in endothelial cells. Blood. 2010;116(13):2395–401.

    PubMed  CAS  Google Scholar 

  124. McCall MN, Kent OA, Yu J, Fox-Talbot K, Zaiman AL, Halushka MK. MicroRNA profiling of diverse endothelial cell types. BMC Med Genet. 2011;4:78.

    CAS  Google Scholar 

  125. Huang F, Fang Z-F, Hu X-Q, Tang L, Zhou S-H, Huang J-P. Overexpression of mir-126 promotes the differentiation of mesenchymal stem cells toward endothelial cells via activation of PI3K/Akt and MAPK/ERK pathways and release of paracrine factors. Biol Chem. 2013;394(9):1223–33.

    PubMed  Google Scholar 

  126. Graf T, Enver T. Forcing cells to change lineages. Nature. 2009;462(7273):587–94.

    PubMed  CAS  Google Scholar 

  127. Margariti A, Winkler B, Karamariti E, et al. Direct reprogramming of fibroblasts into endothelial cells capable of angiogenesis and reendothelialization in tissue-engineered vessels. Proc Natl Acad Sci U S A. 2012;109(34):13793–8.

    PubMed  CAS  Google Scholar 

  128. Li J, Huang NF, Zou J, et al. Conversion of human fibroblasts to functional endothelial cells by defined factors. Arterioscler Thromb Vasc Biol. 2013;33(6):1366–75.

    PubMed  CAS  Google Scholar 

  129. Ginsberg M, James D, Ding B-S, et al. Efficient direct reprogramming of mature amniotic cells into endothelial cells by ETS factors and TGFβ suppression. Cell. 2012;151(3):559–75.

    PubMed  CAS  Google Scholar 

  130. Nam Y-J, Song K, Luo X, et al. Reprogramming of human fibroblasts toward a cardiac fate. Proc Natl Acad Sci U S A. 2013;110(14):5588–93.

    PubMed  CAS  Google Scholar 

  131. Janssen HL, Reesink HW, Lawitz EJ, et al. Treatment of HCV infection by targeting microRNA. N Engl J Med. 2013;368(18):1685–94.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the National Institutes of Health (HL091076, HL115141, and HL117994 to M.W.F.) and a Watkins Cardiovascular Medicine Discovery Award (to M.W.F.).

Conflict of Interest

Xinghui Sun, Nathan Belkin, and Mark W. Feinberg declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Department of Medicine, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, NRB-742F, Boston, MA, 02115, USA

    Xinghui Sun, Nathan Belkin & Mark W. Feinberg

Authors
  1. Xinghui Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nathan Belkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark W. Feinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark W. Feinberg.

Additional information

This article is part of the Topical Collection on Clinical Trials and Their Interpretations

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sun, X., Belkin, N. & Feinberg, M.W. Endothelial MicroRNAs and Atherosclerosis. Curr Atheroscler Rep 15, 372 (2013). https://doi.org/10.1007/s11883-013-0372-2

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11883-013-0372-2

Keywords

Search

Navigation