title: 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.
authors.affiliation: 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].
authors.forename: Andreas
authors.identifier: 000000017798136X
authors.initials: A
authors.lastname: Schober
authors.affiliation: 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].
authors.forename: Maliheh
authors.initials: M
authors.lastname: Nazari-Jahantigh
authors.affiliation: 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.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Kiril
authors.initials: K
authors.lastname: Bidzhekov
authors.affiliation: Department for Experimental Molecular Imaging, RWTH Aachen University, Aachen, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Gremse
authors.affiliation: European Vascular Center Aachen-Maastricht, RWTH Aachen University, Aachen, Germany, and Medical University Maastricht, Maastricht, The Netherlands.
authors.forename: Jochen
authors.initials: J
authors.lastname: Grommes
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Remco T A
authors.initials: RT
authors.lastname: Megens
authors.affiliation: 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.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Heyll
authors.affiliation: Institute for Molecular Cardiovascular Research, Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University, Aachen, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Noels
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hristov
authors.affiliation: Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana, USA.
authors.forename: Shusheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department for Experimental Molecular Imaging, RWTH Aachen University, Aachen, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Kiessling
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.affiliation: 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.
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics*; D002135:Calcium-Binding Proteins; D020212:Carotid Artery Injuries / Q000378:metabolism; D049109:Cell Proliferation; D015536:Down-Regulation; D042783:Endothelial Cells; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology
chemical_list: D001057:Apolipoproteins E; D002135:Calcium-Binding Proteins; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C545201:MIRN126 microRNA, mouse; D035683:MicroRNAs