H19 Induces Abdominal Aortic Aneurysm Development and Progression. Circulation Li, D. Y., Busch, A. n., Jin, H. n., Chernogubova, E. n., Pelisek, J. n., Karlsson, J. n., Sennblad, B. n., Liu, S. n., Lao, S. n., Hofmann, P. n., Bäcklund, A. n., Eken, S. M., Roy, J. n., Eriksson, P. n., Dacken, B. n., Ramanujam, D. n., Dueck, A. n., Engelhardt, S. n., Boon, R. A., Eckstein, H. H., Spin, J. M., Tsao, P. S., Maegdefessel, L. n. 2018


Background -Long noncoding RNAs (lncRNAs) have emerged as critical molecular regulators in various biological processes and diseases. Here we sought to identify and functionally characterize lncRNAs as potential mediators in abdominal aortic aneurysm (AAA) development. Methods -We profiled RNA transcript expression in two murine AAA models, Angiotensin II (ANGII) infusion in ApoE-/- mice (n=8) and porcine pancreatic elastase (PPE) instillation in C57BL/6 wildtype mice (n=12). The lncRNA H19 was identified as one of the most highly up-regulated transcripts in both mouse aneurysm models compared to sham-operated controls. This was confirmed by qRT-PCR and in situ hybridization. Results -Experimental knock-down of H19, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) in vivo, significantly limited aneurysm growth in both models. Upregulated H19 correlated with smooth muscle cell (SMC) content and SMC apoptosis in progressing aneurysms. Importantly, a similar pattern could be observed in human AAA tissue samples, and in a novel preclinical LDLR-/- Yucatan mini-pig aneurysm model. In vitro knock-down of H19 markedly decreased apoptotic rates of cultured human aortic SMCs, while overexpression of H19 had the opposite effect. Notably, H19-dependent apoptosis mechanisms in SMCs appeared to be independent of miR-675, which is embedded in the first exon of the H19 gene. A customized transcription factor array identified hypoxia-inducible factor 1-alpha (HIF1a) as the main downstream effector. Increased SMC apoptosis was associated with cytoplasmic interaction between H19 and HIF1a and sequential p53 stabilization. Additionally, H19 induced transcription of HIF1a via recruiting the transcription factor specificity protein 1 (Sp1) to the promoter region. Conclusions -The lncRNA H19 is a novel regulator of SMC survival in AAA development and progression. Inhibition of H19 expression might serve as a novel molecular therapeutic target for aortic aneurysm disease.

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