TY - JOUR
TI - Pleiotropic effects of laminar flow and statins depend on the
Kruppel-like factor-induced lncRNA MANTIS
AU - Leisegang, Matthias S.
AU - Bibli, Sofia-Iris
AU - Guenther, Stefan and
AU - Pflueger-Mueller, Beatrice
AU - Oo, James A.
AU - Hoeper, Cindy and
AU - Seredinski, Sandra
AU - Yekelchyk, Michail
AU - Schmitz-Rixen, Thomas and
AU - Schuermann, Christoph
AU - Hu, Jiong
AU - Looso, Mario
AU - Sigala,
AU - Fragiska
AU - Boon, Reinier A.
AU - Fleming, Ingrid
AU - Brandes, Ralf P.
JO - EUROPEAN HEART JOURNAL-CARDIOVASCULAR PHARMACOTHERAPY
PY - 2019
VL - 40
TODO - 30
SP - 2523-2533
PB - Oxford University Press
SN - null
TODO - 10.1093/eurheartj/ehz393
TODO - lncRNA; Statin; Laminar flow; ICAM-1; Atherosclerosis
TODO - 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 Aluelement, 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.
ER -