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Nat Med. 2014 Apr;20(4):368-76. doi: 10.1038/nm.3487. Epub 2014 Mar 2.

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

Author information

1
1] Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany. [2] Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany. [3] DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany. [4].
2
1] Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany. [2] Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany. [3].
3
1] Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany. [2] Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany.
4
Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany.
5
Department for Experimental Molecular Imaging, RWTH Aachen University, Aachen, Germany.
6
European Vascular Center Aachen-Maastricht, RWTH Aachen University, Aachen, Germany, and Medical University Maastricht, Maastricht, The Netherlands.
7
Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany.
8
Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA.
9
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
10
1] Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany. [2] Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany. [3] DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany. [4] Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, The Netherlands.

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.

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PMID:
24584117
PMCID:
PMC4398028
DOI:
10.1038/nm.3487
[Indexed for MEDLINE]
Free PMC Article

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