1. Long Noncoding RNA-Enriched Vesicles Secreted by Hypoxic Cardiomyocytes Drive Cardiac Fibrosis
- Author
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Ariana Foinquinos, Angelika Pfanne, Sandra Funcke, Kristian Scherf, Stella M. Raemon-Buettner, Xavier Loyer, Claudia Bang, Annette Just, Stephane Mazlan, Chantal M. Boulanger, Marc N. Hirt, Celina Genschel, Blanche Schroen, Susann Dehmel, Ke Xiao, Thomas Eschenhagen, Steffie Hermans-Beijnsberger, Thomas Thum, Stevan D. Stojanović, Jan Fiedler, Franziska Kenneweg, Katharina Schimmel, RS: Carim - H02 Cardiomyopathy, Cardiologie, RS: CARIM - R2 - Cardiac function and failure, Promovendi CD, and Publica
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0301 basic medicine ,BIOMARKER ,Cardiac fibrosis ,PROGRESSION ,Article ,03 medical and health sciences ,0302 clinical medicine ,lncRNA ,Drug Discovery ,Neat1 ,medicine ,EXTRACELLULAR-MATRIX ,Gene silencing ,Fibroblast ,Gene ,PARASPECKLES ,EXOSOMES ,MESENCHYMAL TRANSITION ,Chemistry ,hypoxia ,lcsh:RM1-950 ,PROLIFERATION ,Cell cycle ,medicine.disease ,Long non-coding RNA ,Cell biology ,Crosstalk (biology) ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,medicine.anatomical_structure ,myocardial infarction ,CARDIOVASCULAR-DISEASE ,030220 oncology & carcinogenesis ,Molecular Medicine ,extracellular vesicles ,Intracellular - Abstract
Long non-coding RNAs (lncRNAs) have potential as novel therapeutic targets in cardiovascular diseases, but detailed information about the intercellular lncRNA shuttling mechanisms in the heart is lacking. Here, we report an important novel crosstalk between cardiomyocytes and fibroblasts mediated by the transfer of lncRNA-enriched extracellular vesicles (EVs) in the context of cardiac ischemia. lncRNA profiling identified two hypoxia-sensitive lncRNAs: ENSMUST00000122745 was predominantly found in small EVs, whereas lncRNA Neat1 was enriched in large EVs in vitro and in vivo. Vesicles were taken up by fibroblasts, triggering expression of profibrotic genes. In addition, lncRNA Neat1 was transcriptionally regulated by P53 under basal conditions and by HIF2A during hypoxia. The function of Neat1 was further elucidated in vitro and in vivo. Silencing of Neat1 in vitro revealed that Neat1 was indispensable for fibroblast and cardiomyocyte survival and affected fibroblast functions (reduced migration capacity, stalled cell cycle, and decreased expression of fibrotic genes). Of translational importance, genetic loss of Neat1 in vivo resulted in an impaired heart function after myocardial infarction highlighting its translational relevance., Graphical Abstract
- Published
- 2019
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