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

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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Figure 1: Loss of endothelial miR-126 impairs endothelial repair in injured arteries.
Figure 2: The miR-126-5p target Dlk1 inhibits endothelial repair.
Figure 3: The passenger strand miR-126-5p promotes endothelial repair.
Figure 4: Mir126 deficiency exacerbates atherosclerosis at nonpredilection sites.
Figure 5: Disturbed flow promotes atherosclerosis by downregulating miR-126-5p.
Figure 6: Administration of miR-126-5p rescues EC proliferation during hyperlipidemic stress.

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Acknowledgements

A.S., F.K. and C.W. are funded by the Deutsche Forschungsgemeinschaft, Germany (FOR809, WE1913/11-2 and SCHO1056/3-2). A.S. and C.W. are funded by the German Federal Ministry of Education and Research (01KU1213A) and by the German Centre for Cardiovascular Research (MHA VD1.2). M.N.-J. was funded by the Interdisciplinary Centre for Clinical Research within the Faculty of Medicine at RWTH Aachen University, Germany. We thank J. Schmidt (University of Illinois) and R.H. Adams (Max-Planck-Institute for Molecular Biomedicine) for providing Dlk1flox and Bmx-CreERT2 mice, respectively. We thank L. Natarelli, L. Pawig, J. Corbalán Campos, R. Soltan, M. Garbe, C. Geissler, P. Hartmann and S. Elbin for technical assistance.

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A.S. and C.W. designed the study, analyzed data and wrote the paper. M.N.-J. performed mouse experiments and collected and processed the histological and qRT-PCR data. Y.W. collected data and performed luciferase assays and mimic treatments. K.B. performed and analyzed in vitro experiments. F.G. and F.K. collected data and performed the fluorescence molecular tomography and computed tomography analyses. J.G. was involved in the analysis of human atherosclerotic lesions. R.T.M. performed the multi-photon microscopy analysis. K.H. collected data and processed the in situ hybridization and immunostaining data. H.N. performed immunoblots and in vitro experiments. M.H. performed flow cytometry analysis and cell culture experiments under flow conditions. S.W. and E.N.O. were involved in study design and contributed to the mouse experiments. A.S. and M.N.-J. contributed equally to the study. All authors discussed the results and commented on the manuscript.

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Correspondence to Andreas Schober or Christian Weber.

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Schober, A., Nazari-Jahantigh, M., Wei, Y. et al. MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. Nat Med 20, 368–376 (2014). https://doi.org/10.1038/nm.3487

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