Abstract
The shear-responsive transcription factor Krüppel-like factor 2 (KLF2) is a critical regulator of endothelial gene expression patterns induced by atheroprotective flow. As microRNAs (miRNAs) post-transcriptionally control gene expression in many pathogenic and physiological processes, we investigated the regulation of miRNAs by KLF2 in endothelial cells. KLF2 binds to the promoter and induces a significant upregulation of the miR-143/145 cluster. Interestingly, miR-143/145 has been shown to control smooth muscle cell (SMC) phenotypes; therefore, we investigated the possibility of transport of these miRNAs between endothelial cells and SMCs. Indeed, extracellular vesicles secreted by KLF2-transduced or shear-stress-stimulated HUVECs are enriched in miR-143/145 and control target gene expression in co-cultured SMCs. Extracellular vesicles derived from KLF2-expressing endothelial cells also reduced atherosclerotic lesion formation in the aorta of ApoE(-/-) mice. Combined, our results show that atheroprotective stimuli induce communication between endothelial cells and SMCs through an miRNA- and extracellular-vesicle-mediated mechanism and that this may comprise a promising strategy to combat atherosclerosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aorta / metabolism
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Aorta / pathology
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Apolipoproteins E / deficiency
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Apolipoproteins E / genetics
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Atherosclerosis / genetics
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Atherosclerosis / metabolism
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Atherosclerosis / pathology
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Cells, Cultured
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Coculture Techniques
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Endothelial Cells / cytology
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Endothelial Cells / metabolism*
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Endothelial Cells / transplantation
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Exosomes / metabolism
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Exosomes / transplantation
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Exosomes / ultrastructure
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Gene Expression Regulation / drug effects
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Human Umbilical Vein Endothelial Cells / cytology
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Kruppel-Like Transcription Factors / genetics*
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Kruppel-Like Transcription Factors / metabolism
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Lovastatin / analogs & derivatives
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Lovastatin / pharmacology
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Mice
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Mice, Knockout
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Microscopy, Confocal
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Microscopy, Electron
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Myocytes, Smooth Muscle / cytology
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Myocytes, Smooth Muscle / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / genetics
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Stress, Mechanical
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Transfection
Substances
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Apolipoproteins E
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KLF2 protein, human
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Kruppel-Like Transcription Factors
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MIRN143 microRNA, human
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MIRN145 microRNA, human
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MicroRNAs
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mevastatin
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Lovastatin