Pleiotropic cardiac functions controlled by ischemia-induced lncRNA H19.

Abstract

Myocardial ischemia induces a multifaceted remodeling process in the heart. Novel therapeutic entry points to counteract maladaptive signalling include the modulation of non-coding RNA molecules such as long non-coding RNA (lncRNA). We here questioned if the lncRNA candidate H19 exhibits regulatory potential in the setting of myocardial infarction. Initial profiling of H19 expression revealed a dynamic expression profile of H19 with upregulation in the acute phase after murine cardiac ischemia. In vitro, we found that oxygen deficiency leads to H19 upregulation in several cardiac cell types. Repression of endogenous H19 caused multiple phenotypes in cultivated murine cardiomyocytes including enhanced cardiomyocyte apoptosis, at least partly through attenuated vitamin D signalling. Unbiased proteome analysis revealed further involvement of H19 in mRNA splicing and translation as well as inflammatory signalling pathways. To study H19 function more precisely, we investigated the phenotype of systemic H19 loss in a genetic mouse model of H19 deletion (H19 KO). Infarcted heart tissue of H19 KO mice showed a massive increase of pro-inflammatory cytokines after ischemia-reperfusion injury (I/R) without significant effects on scar formation or cardiac function but exaggerated cardiac hypertrophy indicating pathological cardiac remodeling. H19-dependent changes in cardiomyocyte-derived extracellular vesicle release and alterations in NF-κB signalling were evident. Cardiac cell fractionation experiments revealed that enhanced H19 expression in the proliferative phase after MI derived mainly from cardiac fibroblasts. Here further research is needed to elucidate its role in fibroblast activation and function. In conclusion, the lncRNA H19 is dynamically regulated after MI and involved in multiple pathways of different cardiac cell types including cardiomyocyte apoptosis and cardiac inflammation.

• Authors: Lisa Hobuß, Ariana Foinquinos, Mira Jung, Franziska Kenneweg, Ke Xiao, Yong Wang, Karina Zimmer, Janet Remke, Annette Just, Juliette Nowak, Arne Schmidt, Andreas Pich, Stephane Mazlan, Stella M Reamon-Buettner, Gustavo Campos Ramos, Stefan Frantz, Janika Viereck, Xavier Loyer, Chantal Boulanger, Kai C Wollert, Jan Fiedler, Thomas Thum
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 146 Pg. 43-59 (09 2020) ISSN: 1095-8584 [Electronic] England
• PMID: 32649928 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• H19 long non-coding RNA
• Proteome
• RNA, Long Noncoding
• Receptors, Calcitriol
• Oxygen

Topics

• Animals
• Cell Line
• Cell Survival (genetics)
• Fibroblasts (metabolism, pathology)
• Gene Expression Regulation
• Genetic Pleiotropy
• HEK293 Cells
• Heart (physiopathology)
• Human Umbilical Vein Endothelial Cells (metabolism)
• Humans
• Inflammation (pathology)
• Mice, Inbred C57BL
• Mice, Knockout
• Models, Biological
• Myocardial Ischemia (genetics, pathology, physiopathology)
• Myocytes, Cardiac (metabolism)
• Oxygen
• Proteome (metabolism)
• RNA, Long Noncoding (genetics, metabolism)
• Receptors, Calcitriol (metabolism)
• Vascular Remodeling (genetics)