title: Endothelial Dicer promotes atherosclerosis and vascular inflammation by miRNA-103-mediated suppression of KLF4.
abstract: MicroRNAs regulate the maladaptation of endothelial cells (ECs) to naturally occurring disturbed blood flow at arterial bifurcations resulting in arterial inflammation and atherosclerosis in response to hyperlipidemic stress. Here, we show that reduced endothelial expression of the RNAse Dicer, which generates almost all mature miRNAs, decreases monocyte adhesion, endothelial C-X-C motif chemokine 1 (CXCL1) expression, atherosclerosis and the lesional macrophage content in apolipoprotein E knockout mice (Apoe(-/-)) after exposure to a high-fat diet. Endothelial Dicer deficiency reduces the expression of unstable miRNAs, such as miR-103, and promotes Krüppel-like factor 4 (KLF4)-dependent gene expression in murine atherosclerotic arteries. MiR-103 mediated suppression of KLF4 increases monocyte adhesion to ECs by enhancing nuclear factor-κB-dependent CXCL1 expression. Inhibiting the interaction between miR-103 and KLF4 reduces atherosclerosis, lesional macrophage accumulation and endothelial CXCL1 expression. Overall, our study suggests that Dicer promotes endothelial maladaptation and atherosclerosis in part by miR-103-mediated suppression of KLF4.
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians University Munich, Pettenkoferstrasse 9, 80336 Munich, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Hartmann
authors.affiliation: Institute for Molecular Cardiovascular Research, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians University Munich, Pettenkoferstrasse 9, 80336 Munich, Germany.
authors.forename: Lucia
authors.initials: L
authors.lastname: Natarelli
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians University Munich, Pettenkoferstrasse 9, 80336 Munich, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Biedersteiner Strasse 29, 80802 Munich, Germany.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians University Munich, Pettenkoferstrasse 9, 80336 Munich, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Biedersteiner Strasse 29, 80802 Munich, Germany.
authors.forename: Maliheh
authors.initials: M
authors.lastname: Nazari-Jahantigh
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians University Munich, Pettenkoferstrasse 9, 80336 Munich, Germany.
authors.forename: Mengyu
authors.initials: M
authors.lastname: Zhu
authors.affiliation: European Vascular Center Aachen-Maastricht, Medical University Maastricht, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands.|European Vascular Center Aachen-Maastricht, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Grommes
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians University Munich, Pettenkoferstrasse 9, 80336 Munich, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Biedersteiner Strasse 29, 80802 Munich, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Steffens
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians University Munich, Pettenkoferstrasse 9, 80336 Munich, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Biedersteiner Strasse 29, 80802 Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig-Maximilians University Munich, Pettenkoferstrasse 9, 80336 Munich, Germany.|Institute for Molecular Cardiovascular Research, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany.|DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Biedersteiner Strasse 29, 80802 Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schober
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism*; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002339:Carotid Arteries / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000235:genetics* / Q000378:metabolism; D059305:Diet, High-Fat; D016894:Endarterectomy, Carotid; D042783:Endothelial Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism; D016328:NF-kappa B; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome; D014657:Vasculitis / Q000235:genetics* / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; C544749:MIRN103 microRNA, human; C555364:MIRN103 microRNA, mouse; D035683:MicroRNAs; D016328:NF-kappa B; C408087:DICER1 protein, human; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
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