Inhibition of the long non-coding RNA NEAT1 protects cardiomyocytes from hypoxia in vitro via decreased pri-miRNA processing
Gidlöf, Olof LU ; Bader, Kerstin ; Celik, Selvi LU ; Grossi, Mario LU ; Nakagawa, Shinichi ; Hirose, Tetsuro ; Metzler, Bernhard ; Olde, Björn LU and Erlinge, David LU
(2020)
In Cell Death and Disease
11(8).
- Abstract
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... (More)
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.
(Less)
- author
- Gidlöf, Olof
LU
; Bader, Kerstin
; Celik, Selvi
LU
; Grossi, Mario
LU
; Nakagawa, Shinichi
; Hirose, Tetsuro
; Metzler, Bernhard
; Olde, Björn
LU
and Erlinge, David
LU
- organization
- publishing date
- 2020-08-01
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Cell Death and Disease
- volume
- 11
- issue
- 8
- article number
- 677
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:32826883
- scopus:85089700796
- ISSN
- 2041-4889
- DOI
- 10.1038/s41419-020-02854-7
- language
- English
- LU publication?
- yes
- id
- d199a4c3-841c-413d-aa8d-4d66e60a14e2
- date added to LUP
- 2021-01-12 08:43:17
- date last changed
- 2024-05-02 00:22:17
@article{d199a4c3-841c-413d-aa8d-4d66e60a14e2,
abstract = {{<p>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.</p>}},
author = {{Gidlöf, Olof and Bader, Kerstin and Celik, Selvi and Grossi, Mario and Nakagawa, Shinichi and Hirose, Tetsuro and Metzler, Bernhard and Olde, Björn and Erlinge, David}},
issn = {{2041-4889}},
language = {{eng}},
month = {{08}},
number = {{8}},
publisher = {{Nature Publishing Group}},
series = {{Cell Death and Disease}},
title = {{Inhibition of the long non-coding RNA NEAT1 protects cardiomyocytes from hypoxia in vitro via decreased pri-miRNA processing}},
url = {{http://dx.doi.org/10.1038/s41419-020-02854-7}},
doi = {{10.1038/s41419-020-02854-7}},
volume = {{11}},
year = {{2020}},
}