MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1

Andreas Schober, Maliheh Nazari-Jahantigh, Yuanyuan Wei, Kiril Bidzhekov, Felix Gremse, Jochen Grommes, Remco T A Megens, Kathrin Heyll, Heidi Noels, Michael Hristov, Shusheng Wang, Fabian Kiessling, Eric N. Olson, Christian Weber

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313 Scopus citations

Abstract

Atherosclerosis, a hyperlipidemia-induced chronic inflammatory process of the arterial wall, develops preferentially at sites where disturbed laminar flow compromises endothelial cell (EC) function. Here we show that endothelial miR-126-5p maintains a proliferative reserve in ECs through suppression of the Notch1 inhibitor delta-like 1 homolog (Dlk1) and thereby prevents atherosclerotic lesion formation. Endothelial recovery after denudation was impaired in Mir126?/? mice because lack of miR-126-5p, but not miR-126-3p, reduced EC proliferation by derepressing Dlk1. At nonpredilection sites, high miR-126-5p levels in endothelial cells confer a proliferative reserve that compensates for the antiproliferative effects of hyperlipidemia, such that atherosclerosis was exacerbated in Mir126?/? mice. In contrast, downregulation of miR-126-5p by disturbed flow abrogated EC proliferation at predilection sites in response to hyperlipidemic stress through upregulation of Dlk1 expression. Administration of miR-126-5p rescued EC proliferation at predilection sites and limited atherosclerosis, introducing a potential therapeutic approach.

Original languageEnglish (US)
Pages (from-to)368-376
Number of pages9
JournalNature medicine
Volume20
Issue number4
DOIs
StatePublished - Apr 2014

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Schober, A., Nazari-Jahantigh, M., Wei, Y., Bidzhekov, K., Gremse, F., Grommes, J., Megens, R. T. A., Heyll, K., Noels, H., Hristov, M., Wang, S., Kiessling, F., Olson, E. N., & Weber, C. (2014). MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. Nature medicine, 20(4), 368-376. https://doi.org/10.1038/nm.3487