Long non-coding RNA H19 regulates endothelial cell aging via inhibition of STAT3 signalling

Patrick Hofmann, Janina Sommer, Kosta Theodorou, Luisa Kirchhof, Ariane Fischer, Yuhuang Li, Ljubica Perisic, Ulf Hedin, Lars Maegdefessel, Stefanie Dimmeler, Reinier A. Boon

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
LanguageEnglish
Pages230-242
JournalCardiovascular Research
Volume115
Issue number1
Early online date13 Aug 2018
DOIs
StatePublished - 2019

Cite this

Hofmann, Patrick ; Sommer, Janina ; Theodorou, Kosta ; Kirchhof, Luisa ; Fischer, Ariane ; Li, Yuhuang ; Perisic, Ljubica ; Hedin, Ulf ; Maegdefessel, Lars ; Dimmeler, Stefanie ; Boon, Reinier A./ Long non-coding RNA H19 regulates endothelial cell aging via inhibition of STAT3 signalling. In: Cardiovascular Research. 2019 ; Vol. 115, No. 1. pp. 230-242
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title = "Long non-coding RNA H19 regulates endothelial cell aging via inhibition of STAT3 signalling",
abstract = "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.",
author = "Patrick Hofmann and Janina Sommer and Kosta Theodorou and Luisa Kirchhof and Ariane Fischer and Yuhuang Li and Ljubica Perisic and Ulf Hedin and Lars Maegdefessel and Stefanie Dimmeler and Boon, {Reinier A.}",
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Hofmann, P, Sommer, J, Theodorou, K, Kirchhof, L, Fischer, A, Li, Y, Perisic, L, Hedin, U, Maegdefessel, L, Dimmeler, S & Boon, RA 2019, 'Long non-coding RNA H19 regulates endothelial cell aging via inhibition of STAT3 signalling' Cardiovascular Research, vol. 115, no. 1, pp. 230-242. DOI: 10.1093/cvr/cvy206, 10.1093/cvr/cvy206

Long non-coding RNA H19 regulates endothelial cell aging via inhibition of STAT3 signalling. / Hofmann, Patrick; Sommer, Janina; Theodorou, Kosta; Kirchhof, Luisa; Fischer, Ariane; Li, Yuhuang; Perisic, Ljubica; Hedin, Ulf; Maegdefessel, Lars; Dimmeler, Stefanie; Boon, Reinier A.

In: Cardiovascular Research, Vol. 115, No. 1, 2019, p. 230-242.

Research output: Contribution to journalArticleAcademicpeer-review

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T1 - Long non-coding RNA H19 regulates endothelial cell aging via inhibition of STAT3 signalling

AU - Hofmann,Patrick

AU - Sommer,Janina

AU - Theodorou,Kosta

AU - Kirchhof,Luisa

AU - Fischer,Ariane

AU - Li,Yuhuang

AU - Perisic,Ljubica

AU - Hedin,Ulf

AU - Maegdefessel,Lars

AU - Dimmeler,Stefanie

AU - Boon,Reinier A.

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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.

AB - 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.

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Hofmann P, Sommer J, Theodorou K, Kirchhof L, Fischer A, Li Y et al. Long non-coding RNA H19 regulates endothelial cell aging via inhibition of STAT3 signalling. Cardiovascular Research. 2019;115(1):230-242. Available from, DOI: 10.1093/cvr/cvy206, 10.1093/cvr/cvy206