Inhibition of the long non-coding RNA NEAT1 protects cardiomyocytes from hypoxia in vitro via decreased pri-miRNA processing.
Animals
Cell Hypoxia
/ genetics
Cytoprotection
/ genetics
Disease Models, Animal
Down-Regulation
/ genetics
Female
Gene Knockdown Techniques
Ischemic Preconditioning
Male
Mice, Inbred C57BL
MicroRNAs
/ genetics
Myocytes, Cardiac
/ metabolism
RNA Processing, Post-Transcriptional
/ genetics
RNA, Long Noncoding
/ genetics
Rats
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
13 08 2020
13 08 2020
Historique:
received:
19
11
2019
accepted:
30
07
2020
revised:
30
07
2020
entrez:
23
8
2020
pubmed:
23
8
2020
medline:
26
3
2021
Statut:
epublish
Résumé
While restoration of coronary blood flow to the ischemic heart is the most effective strategy for reducing infarct size, reperfusion injury represents a significant limiting factor on clinical outcomes in myocardial infarction patients. Ischemic preconditioning (IPC) has been shown to inhibit reperfusion injury and represents an attractive model for studying cardioprotective signal transduction pathways. Long non-coding RNAs (lncRNAs) are a structurally and functionally heterogenous class of RNA transcripts with unknown roles in IPC-induced cardioprotection. Through microarray-based expression profiling of 31,423 lncRNAs in cardiac tissue from IPC mice, we identified the nuclear transcript Neat1 to be rapidly and robustly decreased in response to IPC. siRNA-mediated knock down of Neat1 reduced apoptosis and necrosis in murine cardiomyocytes (CM) and human iPS-derived CMs in response to prolonged hypoxia and hypoxia-reoxygenation, assessed with Annexin V/propidium iodide-staining, a Caspase 3/7 activity assay, LDH release, and western blot for cleaved Caspase 3. Mechanistically, Neat1 was shown to regulate processing of pro-apoptotic microRNA-22 (miR-22) in murine and human CM nuclei using a luciferase reporter assay. Hypoxia-induced downregulation of Neat1 was shown to result in accumulation of unprocessed pri-miRNA and decreased availability of biologically active miRNA, including miR-22. Addition of exogenous synthetic miR-22 reversed the protective effect of Neat1 knock down in human iPS-CM. In conclusion, we have identified the nuclear lncRNA Neat1 as part of a conserved oxygen-sensitive feedback mechanism by regulation of miRNA processing and a potential target in cardioprotection.
Identifiants
pubmed: 32826883
doi: 10.1038/s41419-020-02854-7
pii: 10.1038/s41419-020-02854-7
pmc: PMC7442835
doi:
Substances chimiques
MicroRNAs
0
Mirn22 microRNA, mouse
0
NEAT1 long non-coding RNA, mouse
0
RNA, Long Noncoding
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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