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Olof Gidlöf

Research project participant

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Inhibition of the long non-coding RNA NEAT1 protects cardiomyocytes from hypoxia in vitro via decreased pri-miRNA processing

Author

  • Olof Gidlöf
  • Kerstin Bader
  • Selvi Celik
  • Mario Grossi
  • Shinichi Nakagawa
  • Tetsuro Hirose
  • Bernhard Metzler
  • Björn Olde
  • David Erlinge

Summary, in English

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.

Department/s

  • Cardiology
  • Molecular Epidemiology and Cardiology
  • Molecular Cardiology
  • Cardiovascular Epigenetics
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2020-08-01

Language

English

Publication/Series

Cell Death and Disease

Volume

11

Issue

8

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Cardiac and Cardiovascular Systems

Status

Published

Research group

  • Molecular Epidemiology and Cardiology
  • Molecular Cardiology
  • Cardiovascular Epigenetics

ISBN/ISSN/Other

  • ISSN: 2041-4889