Abstract 311: The Long Non-Coding RNA H19 Regulates Experimental Abdominal Aortic Aneurysm Development and Progression

Abstract

Background: Long noncoding RNAs (lncRNAs) have emerged as critical epigenetic regulators in various biological processes and diseases. Here we sought to identify and functionally characterize the lncRNA H19 as a novel regulator in abdominal aortic aneurysm development. Methods and Results: We profiled RNA transcript expression in two murine abdominal aortic aneurysm models, Angiotensin II (ANGII) infusion in ApoE-/- mice and porcine pancreatic elastase (PPE) instillation in C57BL/6 wildtype mice. 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. Experimental knock-down of H19, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) in vivo , significantly limited aneurysm growth in both models. Upregulated H19 correlated well with smooth muscle cell (SMC) content and its apoptosis in progressing aneurysms. Of importance, 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. Interestingly, H19-dependent cell fate decisions in SMCs appeared independent of miR-675, which is embedded in the first exon of the H19 gene. A customized transcription factor array and proteomic analysis revealed the hypoxia-inducible factor 1-alpha (HIF1A) and interleukin 1 receptor-like 2 (IL1RL2) as the main downstream effectors being regulated via H19. Conclusion: The lncRNA H19 is a novel regulator of SMC survival and aortic inflammation in AAA development and progression. Ultimately inhibition of H19 expression might serve as a novel molecular therapeutic target for aneurysm disease. Key words: Long noncoding RNAs (lncRNAs); abdominal aortic aneurysm; smooth muscle cells (SMCs); Inflammation