Aging-regulated TUG1 is dispensable for endothelial cell function

Gimbel, Anna Theresa; Koziarek, Susanne; Theodorou, Kosta; Schulz, Jana Felicitas; Stanicek, Laura; Kremer, Veerle; Ali, Tamer; Günther, Stefan; Kumar, Sandeep; Jo, Hanjoong; Hübner, Norbert; Maegdefessel, Lars; Dimmeler, Stefanie; Heesch, Sebastiaan van; Boon, Reinier A.

doi:10.1371/journal.pone.0265160

Cited by 5 publications

(3 citation statements)

References 53 publications

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“…48 h post-transfection, RNA was isolated as described earlier. RNA quality control, library preparation, RNA-sequencing and analysis was performed as described in 15 . The related data are available on Gene Expression Omnibus (accession number GSE248795; reviewer token: cxutusselbenlkp; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE248795).…”

Section: Methodsmentioning

confidence: 99%

“…Electrical Cell-substrate Impedance Sensing (ECIS) was performed to assess endothelial barrier integrity and migration after wounding of an endothelial monolayer as described before 30 .…”

Section: Ecismentioning

confidence: 99%

“…Cytoplasmic, nucleoplasmic and chromatin fractions of untransfected HUVECs were isolated as described in 30 .…”

Section: Subcellular Fractionationmentioning

confidence: 99%

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The aging-induced long non-coding RNAMIRIALcontrols endothelial cell and mitochondrial function

Kohnle,

Koziarek,

Warwick

et al. 2024

Preprint

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BackgroundVascular aging is characterized by the progressive deterioration of endothelial function. Long non-coding RNAs (lncRNAs) are critical regulators of gene expression and protein function. However, their involvement in aging-related dysregulation of endothelial cell function remains largely unknown. Here, we aim to characterize the aging-regulated lncRNAMIRIALin endothelial cells.Methods + ResultsWe initially identifiedMirialas an aging-induced lncRNA in RNA sequencing data of mouse cardiac endothelial cells. In human umbilical vein endothelial cells (HUVECs), gapmer-mediated knockdown ofMIRIALled to decreases in proliferation, migration and basal angiogenic sprouting. Additionally,MIRIALknockdown led to increased mitochondrial mass, spare respiratory capacity, and vascular endothelial growth factor (VEGF)-stimulated sprouting. Mechanistically, we demonstrate thatMIRIALforms anRNA·DNA:DNA triple helix (triplex) with a regulatory region of the quiescence-promoting Forkhead Box O1 (FOXO1) gene, thus inducing its expression. The formation of this triplex involves anAluelement within theMIRIALtranscript, representing a previously undescribed mechanism of action for a lncRNA. Further, we generated a globalMirialknockout mouse line of. Angiogenic sprouting of aortic rings fromMirialknockout mice was reduced under basal conditions, but increased after VEGF administration, validating thein vitroangiogenic phenotype. Importantly, cardiac contractile function after acute myocardial infarction is severely reduced inMirialknockout mice, as compared to wild-type littermates.ConclusionsThe lncRNAMIRIALis an aging-induced regulator of endothelial quiescence and metabolism.Abstract Figure

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Section: Methodsmentioning

confidence: 99%

“…Electrical Cell-substrate Impedance Sensing (ECIS) was performed to assess endothelial barrier integrity and migration after wounding of an endothelial monolayer as described before 30 .…”

Section: Ecismentioning

confidence: 99%

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The aging-induced long non-coding RNAMIRIALcontrols endothelial cell and mitochondrial function

Kohnle,

Koziarek,

Warwick

et al. 2024

Preprint

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Detection of cell-type-enriched long noncoding RNAs in atherosclerosis using single-cell techniques: A brief review

Wu,

Yin,

Guo

et al. 2023

Life Sciences

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CTGF is a Modifiable Mediator of Flow-dependent Atherosclerosis under Peripheral Artery Disease Conditions

Kumar

Pokutta-Paskaleva

et al. 2023

Preprint

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Background Peripheral arterial disease (PAD) is the 3rd leading type of atherosclerotic disease (ASD) morbidity. Arterial stiffness is intimately connected to the onset and progression of peripheral artery disease (PAD). The role of arterial stiffening on flow-mediated atherosclerotic plaque formation is not well understood. The objective of this study is to discover endothelial cell (EC) pathways under PAD conditions and test the modifiability of these pathways on ASD. Methods PAD conditions in mice were conferred by partial carotid ligation to induce disturbed Flow (D-flow) in pre-stiffened Fibulin-5 knockout (KO) mice that lack normal elastin function. EC pathways, including Connective tissue growth factor (CTGF/CCN) were quantified by gene analysis and histology. Atherogenic mice had PCSK9 infection + high fat diet. CTGF was inhibited in an EC-specific knockout (ECKOCTGF) and with a CTGF antibody (FG-3149). Human vascular tissue was used to validate PAD biomechanics and CTGF upregulation. Results Biomechanical testing demonstrated that d-flow KO arteries mimic biomechanics of PAD arteries. RNA microarray, qPCR, and immunohistochemistry identified EC plasticity in these arteries compared to WT and KO under stable flow. Under atherogenic conditions, KO arteries demonstrated vulnerable plaques not seen in WT animals. CTGF expression was increased by d-flow, in KO arteries, in aged (18 months) WT arteries, and vascular tissue under d-flow. CTGF inhibition by ECKOCTGF favorably improved plaque characteristics in male but not female animals. FG-3149 treatment of ECWTCTGF male animals delivered similar benefits to plaque characteristics and arterial compliance. Conclusion ECs in PAD arteries exist under a complex hemodynamic environment that integrates stiffness and d-flow into an atherogenic and inflammatory environment. Stiffness + d-flow stimulates precocious onset of EC plasticity and a vulnerable plaque phenotype. CTGF is a matricellular protein that can tune fibro-inflammatory pathways. CTGF is a prominent mediator of D-flow-mediated arterial remodeling and focal atherosclerotic plaque remodeling. Inhibition of CTGF improves plaque phenotype and arterial compliance. CTGF-associated pathways hold promise as therapeutic targets for PAD patients. Key words: Peripheral arterial disease; Flow-mediated atherosclerosis; Arterial stiffness; endothelial cell plasticity; Connective tissue growth factor/CCN2; Fibulin 5

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Aging-regulated TUG1 is dispensable for endothelial cell function

Cited by 5 publications

References 53 publications

The aging-induced long non-coding RNAMIRIALcontrols endothelial cell and mitochondrial function

The aging-induced long non-coding RNAMIRIALcontrols endothelial cell and mitochondrial function

Detection of cell-type-enriched long noncoding RNAs in atherosclerosis using single-cell techniques: A brief review

CTGF is a Modifiable Mediator of Flow-dependent Atherosclerosis under Peripheral Artery Disease Conditions

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