miR-103 promotes endothelial maladaptation by targeting lncWDR59

Lucia Natarelli, Claudia Geißler, Gergely Csaba, Yuanyuan Wei, Mengyu Zhu, Andrea di Francesco, Petra Hartmann, Ralf Zimmer and Andreas Schober ()
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Lucia Natarelli: Ludwig-Maximilians University Munich
Claudia Geißler: Ludwig-Maximilians University Munich
Gergely Csaba: Ludwig-Maximilians University Munich
Yuanyuan Wei: Ludwig-Maximilians University Munich
Mengyu Zhu: Ludwig-Maximilians University Munich
Andrea di Francesco: Ludwig-Maximilians University Munich
Petra Hartmann: Ludwig-Maximilians University Munich
Ralf Zimmer: Ludwig-Maximilians University Munich
Andreas Schober: Ludwig-Maximilians University Munich

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Blood flow at arterial bifurcations and curvatures is naturally disturbed. Endothelial cells (ECs) fail to adapt to disturbed flow, which transcriptionally direct ECs toward a maladapted phenotype, characterized by chronic regeneration of injured ECs. MicroRNAs (miRNAs) can regulate EC maladaptation through targeting of protein-coding RNAs. However, long noncoding RNAs (lncRNAs), known epigenetic regulators of biological processes, can also be miRNA targets, but their contribution on EC maladaptation is unclear. Here we show that hyperlipidemia- and oxLDL-induced upregulation of miR-103 inhibits EC proliferation and promotes endothelial DNA damage through targeting of novel lncWDR59. MiR-103 impedes lncWDR59 interaction with Notch1-inhibitor Numb, therefore affecting Notch1-induced EC proliferation. Moreover, miR-103 increases the susceptibility of proliferating ECs to oxLDL-induced mitotic aberrations, characterized by an increased micronucleic formation and DNA damage accumulation, by affecting Notch1-related β-catenin co-activation. Collectively, these data indicate that miR-103 programs ECs toward a maladapted phenotype through targeting of lncWDR59, which may promote atherosclerosis.

Date: 2018
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DOI: 10.1038/s41467-018-05065-z

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