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Thromb Haemost 2012; 108(04): 616-620
DOI: 10.1160/TH12-07-0491
Theme Issue Article
Schattauer GmbH

Atheroprotective mechanisms of shear stress-regulated microRNAs

Reinier A. Boon
1   Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University, Frankfurt, Germanys
,
Eduard Hergenreider
1   Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University, Frankfurt, Germanys
,
Stefanie Dimmeler
1   Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University, Frankfurt, Germanys
› Author Affiliations
Further Information

Publication History

Received: 16 July 2012

Accepted after minor revision: 22 August 2012

Publication Date:
29 November 2017 (online)

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Summary

MicroRNAs (miRs) are small non-coding RNAs that control gene expression by inhibiting translation or inducing degradation of targeted mRNA. miRs play a crucial role in vascular homeostasis but also during pathophysiological processes. Functionally active endothelial cells maintain homeostasis of the vasculature and protect against cardiovascular disease. The mechanical activation of endothelial cells by laminar shear stress provides a potent atheroprotective effect and reduces endothelial inflammation and cell cycle progression. Laminar shear stress induces profound changes in gene expression and recently was shown to regulate various miRs. The down-regulation of miR-92a by shear stress enhances the expression of the endothelial nitric oxide synthase, whereas the up-regulation of miR-19a contributes to the shear stress-induced inhibition of cell proliferation. In addition, members of the miR-23–27–24 cluster are increased and specifically miR-23b blocks cell cycle progression, whereas miR-27b was shown to reduce endothelial cell repulsive signals. Finally, increased miR-10 expression in atheroprotected regions reduced the inflammatory response of endothelial cells and increased endothelial miR-143/145 levels improved smooth muscle cells functions. Together, the regulation of miRs by shear stress contributes to the anti-inflammatory, cell cycle inhibitory and vasculoprotective effects in endothelial cells.

Keywords

Atherosclerosis - shear stress - angiogenesis and inhibitors - endothelial cells
 

  • References

  • 1 Davies PF. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat Clin Pract Cardiovasc Med 2009; 06: 16-26.
    CrossrefPubMedGoogle Scholar
  • 2 Nigro P, Abe J, Berk BC. Flow shear stress and atherosclerosis: a matter of site specificity. Antioxid Redox Signal 2011; 15: 1405-1414.
    CrossrefPubMedGoogle Scholar
  • 3 Boon RA, Horrevoets AJ. Key transcriptional regulators of the vasoprotective effects of shear stress. Hamostaseologie 2009; 29: 39-40. 1–3.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Iorio MV, Croce CM. MicroRNA dysregulation in cancer: diagnostics, monitoring and therapeutics. A comprehensive review. EMBO Mol Med 2012; 04: 143-159.
    CrossrefPubMedGoogle Scholar
  • 5 Thum T. MicroRNA therapeutics in cardiovascular medicine. EMBO Mol Med 2012; 04: 3-14.
    CrossrefPubMedGoogle Scholar
  • 6 Carthew RW, Sontheimer EJ. Origins and Mechanisms of miRNAs and siRNAs. Cell 2009; 136: 642-655.
    CrossrefPubMedGoogle Scholar
  • 7 Kim VN, Han J, Siomi MC. Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol 2009; 10: 126-139.
    PubMedGoogle Scholar
  • 8 Lewis BP, Burge CB, Bartel DP. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005; 120: 15-20.
    CrossrefPubMedGoogle Scholar
  • 9 Lewis B P, Shih IH, Jones-Rhoades MW. et al. Prediction of mammalian microRNA targets. Cell 2003; 115: 787-798.
    CrossrefPubMedGoogle Scholar
  • 10 Stark A, Brennecke J, Bushati N. et al. Animal MicroRNAs confer robustness to gene expression and have a significant impact on 3'UTR evolution. Cell 2005; 123: 1133-1146.
    CrossrefPubMedGoogle Scholar
  • 11 Xie X, Lu J, Kulbokas EJ. et al. Systematic discovery of regulatory motifs in human promoters and 3' UTRs by comparison of several mammals. Nature 2005; 434: 338-345.
    CrossrefPubMedGoogle Scholar
  • 12 Farh KK, Grimson A, Jan C. et al. The widespread impact of mammalian MicroRNAs on mRNA repression and evolution. Science 2005; 310: 1817-1821.
    CrossrefPubMedGoogle Scholar
  • 13 van Rooij E, Sutherland LB, Thatcher JE. et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci USA 2008; 105: 13027-13032.
    CrossrefPubMedGoogle Scholar
  • 14 Xin M, Small EM, Sutherland LB. et al. MicroRNAs miR-143 and miR-145 modulate cytoskeletal dynamics and responsiveness of smooth muscle cells to injury. Genes Dev 2009; 23: 2166-2178.
    CrossrefPubMedGoogle Scholar
  • 15 Yang WJ, Yang DD, Na S. et al. Dicer is required for embryonic angiogenesis during mouse development. J Biol Chem 2005; 280: 9330-9335.
    CrossrefPubMedGoogle Scholar
  • 16 Giraldez AJ, Cinalli RM, Glasner ME. et al. MicroRNAs regulate brain morphogenesis in zebrafish. Science 2005; 308: 833-838.
    CrossrefPubMedGoogle Scholar
  • 17 Kuehbacher A, Urbich C, Zeiher AM. et al. Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis. Circ Res 2007; 101: 59-68.
    CrossrefPubMedGoogle Scholar
  • 18 Suarez Y, Fernandez-Hernando C, Pober JS. et al. Dicer dependent microRNAs regulate gene expression and functions in human endothelial cells. Circ Res 2007; 100: 1164-1173.
    CrossrefPubMedGoogle Scholar
  • 19 Suarez Y, Fernandez-Hernando C, Yu J. et al. Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis. Proc Natl Acad Sci USA 2008; 105: 14082-14087.
    CrossrefPubMedGoogle Scholar
  • 20 Boon RA, Dimmeler S. MicroRNAs and aneurysm formation. Trends Cardiovasc Med 2012; 21: 172-177.
    PubMedGoogle Scholar
  • 21 Small EM, Frost RJ, Olson EN. MicroRNAs add a new dimension to cardiovascular disease. Circulation 2010; 121: 1022-1032.
    CrossrefPubMedGoogle Scholar
  • 22 García-Cardeña G, Comander J, Anderson KR. et al. Biomechanical activation of vascular endothelium as a determinant of its functional phenotype. Proc Natl Acad Sci USA 2001; 98: 4478-4485.
    CrossrefPubMedGoogle Scholar
  • 23 Dekker RJ, van Soest S, Fontijn RD. et al. Prolonged fluid shear stress induces a distinct set of endothelial cell genes, most specifically lung Krüppel-like factor (KLF2). Blood 2002; 100: 1689-1698.
    CrossrefPubMedGoogle Scholar
  • 24 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 USA 2010; 107: 3240-3244.
    CrossrefPubMedGoogle Scholar
  • 25 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 USA 2010; 107: 3234-3239.
    CrossrefPubMedGoogle Scholar
  • 26 Weber M, Baker MB, Moore JP. et al. MiR-21 is induced in endothelial cells by shear stress and modulates apoptosis and eNOS activity. Biochem Biophys Res Commun 2010; 393: 643-648.
    CrossrefPubMedGoogle Scholar
  • 27 Holliday CJ, Ankeny RF, Jo H. et al. Discovery of shear- and side-specific mRNAs and miRNAs in human aortic valvular endothelial cells. Am J Physiol Heart Circ Physiol 2011; 301: H856-867.
    CrossrefPubMedGoogle Scholar
  • 28 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: H1762-1769.
    CrossrefPubMedGoogle Scholar
  • 29 Fang Y, Shi C, Manduchi E. et al. MicroRNA-10a regulation of proinflammatory phenotype in athero-susceptible endothelium in vivo and in vitro. Proc Natl Acad Sci USA 2010; 107: 13450-13455.
    CrossrefPubMedGoogle Scholar
  • 30 Wu W, Xiao H, Laguna-Fernandez A. et al. Flow-Dependent Regulation of Kruppel-Like Factor 2 Is Mediated by MicroRNA-92a. Circulation 2011; 124: 633-641.
    CrossrefPubMedGoogle Scholar
  • 31 Fang Y, Davies PF. Site-specific microRNA-92a regulation of Kruppel-like factors 4 and 2 in atherosusceptible endothelium. Arterioscler Thromb Vasc Biol 2012; 32: 979-987.
    CrossrefPubMedGoogle Scholar
  • 32 Bonauer A, Carmona G, Iwasaki M. et al. MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science 2009; 324: 1710-1713.
    CrossrefPubMedGoogle Scholar
  • 33 Urbich C, Dernbach E, Reissner A. et al. Shear stress-induced endothelial cell migration involves integrin signaling via the fibronectin receptor subunits alpha(5) and beta(1). Arterioscler Thromb Vasc Biol 2002; 22: 69-75.
    CrossrefPubMedGoogle Scholar
  • 34 Doebele C, Bonauer A, Fischer A. et al. Members of the microRNA-17–92 cluster exhibit a cell-intrinsic antiangiogenic function in endothelial cells. Blood 2010; 115: 4944-4950.
    CrossrefPubMedGoogle Scholar
  • 35 Zhou Q, Gallagher R, Ufret-Vincenty R. et al. Regulation of angiogenesis and choroidal neovascularization by members of microRNA-23∼27∼24 clusters. Proc Natl Acad Sci USA 2011; 108: 8287-8292.
    CrossrefPubMedGoogle Scholar
  • 36 Urbich C, Kaluza D, Fromel T. et al. MicroRNA-27a/b controls endothelial cell repulsion and angiogenesis by targeting semaphorin 6A. Blood 2012; 119: 1607-1616.
    CrossrefPubMedGoogle Scholar
  • 37 Hergenreider E, Heydt S, Treguer K. et al. Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nat Cell Biol 2012; 14: 249-256.
    CrossrefPubMedGoogle Scholar
  • 38 Chen WJ, Yin K, Zhao GJ. et al. The magic and mystery of MicroRNA-27 in atherosclerosis. Atherosclerosis 2012; 222: 314-323.
    CrossrefPubMedGoogle Scholar
  • 39 Karbiener M, Fischer C, Nowitsch S. et al. microRNA miR-27b impairs human adipocyte differentiation and targets PPARgamma. Biochem Biophys Res Commun 2009; 390: 247-251.
    CrossrefPubMedGoogle Scholar
  • 40 Ameshima S, Golpon H, Cool CD. et al. Peroxisome proliferator-activated receptor gamma (PPARgamma) expression is decreased in pulmonary hypertension and affects endothelial cell growth. Circ Res 2003; 92: 1162-1169.
    CrossrefPubMedGoogle Scholar
  • 41 Biyashev D, Veliceasa D, Topczewski J. et al. miR-27b controls venous specification and tip cell fate. Blood 2012; 119: 2679-2687.
    CrossrefPubMedGoogle Scholar
  • 42 Ho J, Pandey P, Schatton T. et al. The pro-apoptotic protein Bim is a microRNA target in kidney progenitors. J Am Soc Nephrol 2011; 22: 1053-1063.
    CrossrefPubMedGoogle Scholar
  • 43 Zhou J, Wang KC, Wu W. et al. MicroRNA-21 targets peroxisome proliferators-activated receptor-alpha in an autoregulatory loop to modulate flow-induced endothelial inflammation. Proc Natl Acad Sci USA 2011; 108: 10355-10360.
    CrossrefPubMedGoogle Scholar
  • 44 Wang S, Aurora AB, Johnson BA. et al. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell 2008; 15: 261-271.
    CrossrefPubMedGoogle Scholar
  • 45 Zernecke A, Bidzhekov K, Noels H. et al. Delivery of MicroRNA-126 by Apoptotic Bodies Induces CXCL12-Dependent Vascular Protection. Sci Signal 2009; 02: ra81.
    PubMedGoogle Scholar
  • 46 Nicoli S, Standley C, Walker P. et al. MicroRNA-mediated integration of haemodynamics and Vegf signalling during angiogenesis. Nature 2010; 464: 1196-1200.
    CrossrefPubMedGoogle Scholar
  • 47 Cordes KR, Sheehy NT, White MP. et al. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature 2009; 460: 705-710.
    PubMedGoogle Scholar
  • 48 Boettger T, Beetz N, Kostin S. et al. Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the Mir143/145 gene cluster. J Clin Invest 2009; 119: 2634-2647.
    CrossrefPubMedGoogle Scholar
  • 49 Elia L, Quintavalle M, Zhang J. et al. The knockout of miR-143 and -145 alters smooth muscle cell maintenance and vascular homeostasis in mice: correlates with human disease. Cell Death Differ 2009; 16: 1590-1598.
    CrossrefPubMedGoogle Scholar
  • 50 Boon RA, Leyen TA, Fontijn RD. et al. KLF2-induced actin shear fibers control both alignment to flow and JNK signaling in vascular endothelium. Blood 2010; 115: 2533-2542.
    CrossrefPubMedGoogle Scholar