miR-103 promotes endothelial maladaptation by targeting lncWDR59

• Published in: Nature communications Vol. 9; no. 1; pp. 2645 - 15
• Main Authors: Natarelli, Lucia, Geißler, Claudia, Csaba, Gergely, Wei, Yuanyuan, Zhu, Mengyu, di Francesco, Andrea, Hartmann, Petra, Zimmer, Ralf, Schober, Andreas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.07.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 14/19; 14/32; 38/39; 38/47; 38/61; 38/91; 49/109; 631/337/1427/2122; 631/337/384/2568; 631/337/384/331; 631/80/83; 692/4019/592/75; 82/29; Animals; Arteriosclerosis; Atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - pathology; Base Sequence; beta Catenin - metabolism; Bifurcations; Biological activity; Blood flow; Cell Proliferation; Damage accumulation; Deoxyribonucleic acid; DNA; DNA Damage; Endothelial cells; Endothelial Cells - metabolism; Epigenetics; Gene Expression Regulation; HMGB Proteins - metabolism; Humanities and Social Sciences; Humans; Hyperlipidemia; Lipoproteins, LDL; Membrane Proteins - metabolism; Mice; Micronuclei, Chromosome-Defective; MicroRNAs - genetics; MicroRNAs - metabolism; miRNA; multidisciplinary; Nerve Tissue Proteins - metabolism; Notch1 protein; NUMB protein; Phenotypes; Proteins; Receptors, Notch - metabolism; Regeneration; Regulators; Ribonuclease III - metabolism; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Science; Science (multidisciplinary); Signal Transduction; SOXF Transcription Factors - metabolism; Transcription; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05065-z

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. MicroRNAs play important roles in endothelial cells injury, proliferation and maladaptation by negatively regulating posttranscriptional gene expression. Here the authors uncover the role of the long non coding RNA lncWDR59, target of miR-103, in endothelial maladaptation.