TY  - JOUR
A1  - Hofmann, Patrick
A1  - Sommer, Janina
A1  - Theodorou, Kosta
A1  - Kirchhof, Luisa
A1  - Fischer, Ariane
A1  - Li, Yuhuang
A1  - Perisic, Ljubica
A1  - Hedin, Ulf
A1  - Mägdefessel, Lars
A1  - Dimmeler, Stefanie
A1  - Boon, Reinier
T1  - Long non-coding RNA H19 regulates endothelial cell aging via inhibition of STAT3 signalling
T2  - Cardiovascular research
N2  - Aims: Long non-coding RNAs (lncRNAs) have been shown to regulate numerous processes in the human genome, but the function of these transcripts in vascular aging is largely unknown. We aim to characterize the expression of lncRNAs in endothelial aging and analyse the function of the highly conserved lncRNA H19.
Methods and results: H19 was downregulated in endothelium of aged mice. In human, atherosclerotic plaques H19 was mainly expressed by endothelial cells and H19 was significantly reduced in comparison to healthy carotid artery biopsies. Loss of H19 led to an upregulation of p16 and p21, reduced proliferation and increased senescence in vitro. Depletion of H19 in aortic rings of young mice inhibited sprouting capacity. We generated endothelial-specific inducible H19 deficient mice (H19iEC-KO), resulting in increased systolic blood pressure compared with control littermates (Ctrl). These H19iEC-KO and Ctrl mice were subjected to hindlimb ischaemia, which showed reduced capillary density in H19iEC-KO mice. Mechanistically, exon array analysis revealed an involvement of H19 in IL-6 signalling. Accordingly, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 were upregulated upon H19 depletion. A luciferase reporter screen for differential transcription factor activity revealed STAT3 as being induced upon H19 depletion and repressed after H19 overexpression. Furthermore, depletion of H19 increased the phosphorylation of STAT3 at TYR705 and pharmacological inhibition of STAT3 activation abolished the effects of H19 silencing on p21 and vascular cell adhesion molecule 1 expression as well as proliferation.
Conclusion: These data reveal a pivotal role for the lncRNA H19 in controlling endothelial cell aging.
KW  - Endothelium
KW  - Inflammation
KW  - Senescence
KW  - Non-coding RNA
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/52763
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-527630
SN  - 1755-3245
SN  - 0008-6363
N1  - This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
VL  - 115
IS  - 1
SP  - 230
EP  - 242
PB  - Oxford University Press
CY  - Oxford
ER  -