Abstract 13641: The Long-Non-Coding RNA Snhg12 Is Dysregulated in Heart Failure and Controls Endothelial Cell and Cardiomyocyte Function

• Published in: Circulation (New York, N.Y.) Vol. 138; no. Suppl_1 Suppl 1; p. A13641
• Main Authors: Aslan, Galip S, Drachsler, Moritz, Meder, Benjamin, Boeckel, Jes N, Katus, Hugo A, Bär, Christian, Thum, Thomas, Zeiher, Andreas M, Lucas, Tina, Manavski, Yosif, Dimmeler, Stefanie
• Format: Journal Article
• Language: English
• Published: by the American College of Cardiology Foundation and the American Heart Association, Inc 06.11.2018
• ISSN: 0009-7322; 1524-4539

BackgroundRNA sequencing revealed that the majority of the human genome is transcribed as non-coding transcripts, which mostly consist of long non-coding RNAs (lncRNAs). Although some lncRNAs were shown to control biological processes, their function in cardiovascular diseases is still largely unexplored. Here we characterized lncRNA expression in cardiac tissue of patients with heart failure and explored the function of the regulated candidates.ResultsRNA sequencing identified differentially regulated IncRNAs in heart failure samples in comparison to healthy controls (n=10 per group, p<0.01). Among the significantly regulated transcripts, Snhg12, which was profoundly down-regulated (4.3 fold) showed the highest expression in iPS-derived human cardiomyocytes (hiPSC-CM) (N=3). Since Snhg12 was also highly expressed in endothelial cells and fibroblasts, we explored its function in all cell types by using Gapmer-mediated silencing. Silencing of Snhg12 (60 % inhibition) lead to increased tube formation (n=9; p<0.05) and angiogenic sprouting of HUVECs (n=8; p<0.01) and reduced hypertrophy of hiPSC-CM (N≥3, p<0.05). Fibroblast proliferation and collagen production was not affected. Since the Snhg12 locus hosts four different non-coding snoRNAs, which are fundamental for ribosomal functions, we determined the regulation of these RNAs. Indeed, silencing of Snhg12 lead to an upregulation of snoRNA-61 in HUVEC, but the other three hosted snoRNAs remain unchanged. Since snoRNA functions in angiogenesis are unexplored, we determined the effect of snoRNA-61. Indeed, Gapmer-mediated silencing of snoRNA-61, decreased cell viability, angiogenic sprouting and tube formation of HUVECs (n=4; p<0.05). In conclusion, Snhg12 is downregulated in heart failure patients. Silencing of Snhg12 increased angiogenic functions of HUVECs and prevented cardiomyocyte hypertrophy. The pro-angiogenic effect of Snhg12 silencing might be mediated by the up-regulated of snoRNA-61, which promoted endothelial cell sprouting. The down-regulation of Snhg12 during heart failure may present a compensatory mechanism.