Long Noncoding RNA-Enriched Vesicles Secreted by Hypoxic Cardiomyocytes Drive Cardiac Fibrosis

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...

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Vydáno v:Molecular therapy. Nucleic acids Ročník 18; s. 363 - 374
Hlavní autoři: Kenneweg, Franziska, Bang, Claudia, Xiao, Ke, Boulanger, Chantal M., Loyer, Xavier, Mazlan, Stephane, Schroen, Blanche, Hermans-Beijnsberger, Steffie, Foinquinos, Ariana, Hirt, Marc N., Eschenhagen, Thomas, Funcke, Sandra, Stojanovic, Stevan, Genschel, Celina, Schimmel, Katharina, Just, Annette, Pfanne, Angelika, Scherf, Kristian, Dehmel, Susann, Raemon-Buettner, Stella M., Fiedler, Jan, Thum, Thomas
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Elsevier Inc 06.12.2019
Elsevier Limited
American Society of Gene & Cell Therapy
Elsevier
Témata:
Cardiomyocytes
Cardiovascular diseases
Cell cycle
Cell migration
Experiments
extracellular vesicles
Fibroblasts
Fibrosis
Gene expression
Heart
Hypoxia
Ischemia
lncRNA
MicroRNAs
Microscopy
Myocardial infarction
Nanoparticles
Neat1
Ostomy
p53 Protein
Ribonucleic acid
RNA
Studies
Therapeutic applications
Transcription
Translation
Vesicles
Germany
hypoxia
lncRNA
extracellular vesicles
Neat1
myocardial infarction
ISSN:2162-2531, 2162-2531
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Shrnutí: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. [Display omitted]
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These authors contributed equally to this work.
ISSN:2162-2531
2162-2531
DOI:10.1016/j.omtn.2019.09.003