Matthias S Leisegang1,2, Sofia-Iris Bibli2,3, Stefan Günther4, Beatrice Pflüger-Müller1,2, James A Oo1,2, Cindy Höper1,2, Sandra Seredinski1,2, Michail Yekelchyk4, Thomas Schmitz-Rixen5, Christoph Schürmann1,2, Jiong Hu2,3, Mario Looso4, Fragiska Sigala6, Reinier A Boon2,7,8, Ingrid Fleming2,3, Ralf P Brandes1,2. 1. Institute for Cardiovascular Physiology, Goethe University, Theodor-Stern-Kai 7, Frankfurt, Germany. 2. German Center of Cardiovascular Research (DZHK), Partner Site RheinMain, Theodor Stern-Kai 7, Frankfurt, Germany. 3. Institute for Vascular Signalling, Goethe University, Theodor Stern-Kai 7, Frankfurt, Germany. 4. Max-Planck-Institute for Heart and Lung Research, ECCPS Bioinformatics and Sequencing Facility, Ludwigstr. 43, Bad Nauheim, Germany. 5. Department of Vascular and Endovascular Surgery, Goethe University, Theodor-Stern-Kai 7, Frankfurt, Germany. 6. 1st Department of Propaedeutic Surgery, University of Athens Medical School, Hippocration Hospital, Etheros 7-9, Athens, Greece. 7. Institute of Cardiovascular Regeneration, Goethe University, Frankfurt, Theodor-Stern-Kai 7, Germany. 8. Department of Physiology, VU University Medical Center, De Boelelaan 1118, HV Amsterdam, the Netherlands.
Abstract
AIMS: To assess the functional relevance and therapeutic potential of the pro-angiogenic long non-coding RNA MANTIS in vascular disease development. METHODS AND RESULTS: RNA sequencing, CRISPR activation, overexpression, and RNAi demonstrated that MANTIS, especially its Alu-element, limits endothelial ICAM-1 expression in different types of endothelial cells. Loss of MANTIS increased endothelial monocyte adhesion in an ICAM-1-dependent manner. MANTIS reduced the binding of the SWI/SNF chromatin remodelling factor BRG1 at the ICAM-1 promoter. The expression of MANTIS was induced by laminar flow and HMG-CoA-reductase inhibitors (statins) through mechanisms involving epigenetic rearrangements and the transcription factors KLF2 and KLF4. Mutation of the KLF binding motifs in the MANTIS promoter blocked the flow-induced MANTIS expression. Importantly, the expression of MANTIS in human carotid artery endarterectomy material was lower compared with healthy vessels and this effect was prevented by statin therapy. Interestingly, the protective effects of statins were mediated in part through MANTIS, which was required to facilitate the atorvastatin-induced changes in endothelial gene expression. Moreover, the beneficial endothelial effects of statins in culture models (spheroid outgrowth, proliferation, telomerase activity, and vascular organ culture) were lost upon knockdown of MANTIS. CONCLUSION: MANTIS is tightly regulated by the transcription factors KLF2 and KLF4 and limits the ICAM-1 mediated monocyte adhesion to endothelial cells and thus potentially atherosclerosis development in humans. The beneficial effects of statin treatment and laminar flow are dependent on MANTIS. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: To assess the functional relevance and therapeutic potential of the pro-angiogenic long non-coding RNA MANTIS in vascular disease development. METHODS AND RESULTS: RNA sequencing, CRISPR activation, overexpression, and RNAi demonstrated that MANTIS, especially its Alu-element, limits endothelial ICAM-1 expression in different types of endothelial cells. Loss of MANTIS increased endothelial monocyte adhesion in an ICAM-1-dependent manner. MANTIS reduced the binding of the SWI/SNF chromatin remodelling factor BRG1 at the ICAM-1 promoter. The expression of MANTIS was induced by laminar flow and HMG-CoA-reductase inhibitors (statins) through mechanisms involving epigenetic rearrangements and the transcription factors KLF2 and KLF4. Mutation of the KLF binding motifs in the MANTIS promoter blocked the flow-induced MANTIS expression. Importantly, the expression of MANTIS in human carotid artery endarterectomy material was lower compared with healthy vessels and this effect was prevented by statin therapy. Interestingly, the protective effects of statins were mediated in part through MANTIS, which was required to facilitate the atorvastatin-induced changes in endothelial gene expression. Moreover, the beneficial endothelial effects of statins in culture models (spheroid outgrowth, proliferation, telomerase activity, and vascular organ culture) were lost upon knockdown of MANTIS. CONCLUSION: MANTIS is tightly regulated by the transcription factors KLF2 and KLF4 and limits the ICAM-1 mediated monocyte adhesion to endothelial cells and thus potentially atherosclerosis development in humans. The beneficial effects of statin treatment and laminar flow are dependent on MANTIS. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: James A Oo; Barnabas Irmer; Stefan Günther; Timothy Warwick; Katalin Pálfi; Judit Izquierdo Ponce; Tom Teichmann; Beatrice Pflüger-Müller; Ralf Gilsbach; Ralf P Brandes; Matthias S Leisegang Journal: Sci Rep Date: 2020-11-05 Impact factor: 4.379