Pleiotropic effects of laminar flow and statins depend on the Krüppel-like factor-induced lncRNA MANTIS

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.

Effect of statin therapy on plasma C-type Natriuretic Peptides and Endothelin-1 in males with and without symptomatic coronary artery disease

“…First, findings from in vitro cell studies (mostly of umbilical venous origin) may not recapitulate physiology 20 . Although in vivo studies of the molecular events underpinning vascular homeostasis continue to support the www.nature.com/scientificreports www.nature.com/scientificreports/ important role of Klf2 2,20 and/or its downstream targets 21 , with one exception 21 none have explored the in vivo effects of statins on these molecular pathways in arterial tissues from humans 2 . In experimental animals, two studies have specifically addressed the role of CNP in statin's actions in vivo.…”

“…None was receiving medication. Body mass index (18)(19)(20)(21)(22)(23)(24)(25), systolic (<140 mmHg) and diastolic (<90 mmHg) blood pressure were normal. All had a normal blood lipid profile.…”

Expedition to the missing link: Long noncoding RNAs in cardiovascular diseases

“…Interestingly, statins also mediate their atheroprotective effects, at least partially, through MANTIS. 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 [90].…”

The Long Non-coding Road to Atherosclerosis

“…lncRNA MANTIS (LncRNA n342419) also mediates vascular protection in trans via its interaction with SWI/SNF chromatin remodeling factor BRG1. This enables BRG1-promoter binding to angiogenic genes, such as SOX18 [45], and on the other hand, hinders BRG1 interaction with the promoter region of monocyte adhesion factor ICAM-1 [46]. As for NEXN-AS1, statins also increased MANTIS expression in human umbilical vein endothelial cells (HUVECs) and prevented reduced MANTIS expression in human artery endarterectomy compared with healthy vessels [46].…”