Long non-coding RNA MANTIS is an important regulator of the endothelial angiogenic function. Here, we sought to determine the mechanisms of MANTIS gene regulation for endothelial function during vascular disease development. Exposure of human umbilical vein endothelial cells to laminar flow or to HMG Co-A reductase inhibitors (statins) induced the expression of lncRNA MANTIS. MANTIS upregulation was caused by the transcription factors KLF2 and KLF4. Mutation of specific KLF binding motifs on the MANTIS promoter abolished the induction. RNA-Sequencing after laminar shear stress demonstrated that MANTIS repressed ICAM-1 gene expression. Consequently, MANTIS was required for endothelial flow alignment and its knockdown increased monocyte adhesion to endothelial cells, which was blocked by ICAM-1 antibodies. CRISPR activation and RNAi confirmed the findings. Mechanistically, the observed regulation was an effect of MANTIS Alu element, blocking the binding of the chromatin remodelling factor BRG1 to the ICAM-1 promoter. These effects were also seen in a putative mouse homologue of MANTIS in murine endothelial cells and murine retina. In the human situation, MANTIS was downregulated in atherosclerotic carotid arteries from patients with >85% stenosis; an effect that was reversed in patients under statin therapy. Moreover, MANTIS expression positively correlated to KLF2 and KLF4, and negatively to ICAM-1 in the human cohort. Expression of MANTIS is tightly regulated by KLF2 and KLF4 in atherosclerotic plaques, in response to shear stress and statin treatment. MANTIS upregulation limits ICAM-1 expression, which affects monocyte adhesion to endothelial cells. MANTIS might regulate the initiation step of atherogenesis in humans.
Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCB324
Poster Communications: Long non-coding RNA MANTIS is induced by statins and limits monocyte adhesion to human endothelial cells
M. S. Leisegang1,2, S. Bibli3,2, S. Günther4, B. Pflüger-Müller1,2, J. A. Oo1,2, J. Hu3,2, F. Sigala5, R. A. Boon6,2, I. Fleming3,2, R. Brandes1,2
1. Institute for Cardiovascular Physiology, Goethe-University Frankfurt, Frankfurt am Main, Germany. 2. Partner Site RheinMain, German Center of Cardiovascular Research (DZHK), Frankfurt, Germany. 3. Institute of Vascular Signalling, Goethe-University Frankfurt, Frankfurt, Germany. 4. ECCPS Bioinformatics and Sequencing Facility, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany. 5. 1st Department of Propaedeutic Surgery, University of Athens Medical School, Hippocration Hospital, Athens, Greece. 6. Institute of Cardiovascular Regeneration, Goethe-University, Frankfurt, Germany.
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Where applicable, experiments conform with Society ethical requirements.