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

Research output: Contribution to journalArticle

273 Citations (Scopus)

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 - 2014

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Endothelial cells
MicroRNAs
Atherosclerosis
Endothelial Cells
Cell proliferation
Cell Proliferation
Hyperlipidemias
Laminar flow
Up-Regulation
Down-Regulation
Recovery

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Schober, A., Nazari-Jahantigh, M., Wei, Y., Bidzhekov, K., Gremse, F., Grommes, J., ... 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

MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. / Schober, Andreas; Nazari-Jahantigh, Maliheh; Wei, Yuanyuan; Bidzhekov, Kiril; Gremse, Felix; Grommes, Jochen; Megens, Remco T A; Heyll, Kathrin; Noels, Heidi; Hristov, Michael; Wang, Shusheng; Kiessling, Fabian; Olson, Eric N.; Weber, Christian.

In: Nature Medicine, Vol. 20, No. 4, 2014, p. 368-376.

Research output: Contribution to journalArticle

Schober, A, Nazari-Jahantigh, M, Wei, Y, Bidzhekov, K, Gremse, F, Grommes, J, Megens, RTA, Heyll, K, Noels, H, Hristov, M, Wang, S, Kiessling, F, Olson, EN & Weber, C 2014, 'MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1', Nature Medicine, vol. 20, no. 4, pp. 368-376. https://doi.org/10.1038/nm.3487
Schober A, Nazari-Jahantigh M, Wei Y, Bidzhekov K, Gremse F, Grommes J et al. MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. Nature Medicine. 2014;20(4):368-376. https://doi.org/10.1038/nm.3487
Schober, Andreas ; Nazari-Jahantigh, Maliheh ; Wei, Yuanyuan ; Bidzhekov, Kiril ; Gremse, Felix ; Grommes, Jochen ; Megens, Remco T A ; Heyll, Kathrin ; Noels, Heidi ; Hristov, Michael ; Wang, Shusheng ; Kiessling, Fabian ; Olson, Eric N. ; Weber, Christian. / MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. In: Nature Medicine. 2014 ; Vol. 20, No. 4. pp. 368-376.
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