MicroRNA-1265 p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk 1

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 ©2014 Nature America, Inc. All rights reserved. Reprints and permissions information is available online at http://www.nature.com/reprints/index.html Correspondence should be addressed to A.S. (aschober@med.lmu.de) or C.W. (chweber@med.lmu.de). 9These authors contributed equally to this work. Accession codes. The microarray data have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus database under accession number GSE34262. Note: Any Supplementary Information and Source Data files are available in the online version of the paper. AUTHOR CONTRIBUTIONS 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 multiphoton 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. COMPETING FINANCIAL INTERESTS The authors declare no competing financial interests. HHS Public Access Author manuscript Nat Med. Author manuscript; available in PMC 2015 April 15. Published in final edited form as: Nat Med. 2014 April ; 20(4): 368–376. doi:10.1038/nm.3487. A uhor M anscript