下调和上调
缺血
长非编码RNA
细胞生物学
心功能曲线
生物
表型
小RNA
刺猬信号通路
癌症研究
内科学
医学
信号转导
心力衰竭
基因
生物化学
作者
Lisa Hobuß,Ariana Foinquinos,Mira Jung,Franziska Kenneweg,Xiaoyan Ke,Yong Wang,Karina Zimmer,Janet Remke,Annette Just,Juliette Nowak,A Schmidt,Andreas Pich,S.M.I. Mazlan,Stella Marie Reamon-Buettner,Gustavo Ramos,Stefan Frantz,Janika Viereck,Xavier Loyer,Chantal M. Boulanger,Kai C. Wollert,Jan Fiedler,Thomas Thum
标识
DOI:10.1016/j.yjmcc.2020.07.001
摘要
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.
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