Long non-coding RNA H19 regulates endothelial cell aging via inhibition of Stat3 signaling.

Hofmann P1,2, Sommer J1, Theodorou K1, Kirchhof L1, Fischer A1, Li Y3,4, Perisic L5, Hedin U5, Maegdefessel L3,4,6, Dimmeler S1,2, Boon RA1,2,7
Source: Cardiovasc Res
Publication Date: ()
Issue: :
Cells used in publication:
Endothelial, umbilical vein, human (HUVEC)
Species: human
Tissue Origin: vein



Long noncoding 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 analyze 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 to control littermates (Ctrl). These H19iEC-KO and Ctrl mice were subjected to hindlimb ischemia, which showed reduced capillary density in H19iEC-KO mice. Mechanistically, exon array analysis revealed an involvement of H19 in IL-6 signaling. Accordingly, ICAM-1 and VCAM-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 VCAM-1 expression as well as proliferation.