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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

433 Citations (Web of Science)

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
Pages (from-to)368-+
JournalNature Medicine
Volume20
Issue number4
DOIs
Publication statusPublished - Apr 2014

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