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dc.date.accessioned2020-05-22T18:14:45Z
dc.date.available2020-05-22T18:14:45Z
dc.date.created2019-12-28T16:05:30Z
dc.date.issued2019
dc.identifier.citationMariero, Lars Henrik Torp, May-Kristin Heiestad, Christina Mathisen Baysa, Anton Li, Yuchuan Valen, Guro Vaage, Ingvar Jarle Stensløkken, Kåre-Olav . Inhibiting nucleolin reduces inflammation induced by mitochondrial DNA in cardiomyocytes exposed to hypoxia and reoxygenation. British Journal of Pharmacology. 2019, 1-13
dc.identifier.urihttp://hdl.handle.net/10852/76090
dc.description.abstractBackground and purpose Cellular debris causes sterile inflammation after myocardial infarction. Mitochondria constitute about 30 percent of the human heart. Mitochondrial DNA (mtDNA) is a damage‐associated‐molecular‐pattern that induce injurious sterile inflammation. Little is known about mtDNA's inflammatory signalling pathways in cardiomyocytes and how mtDNA is internalized to associate with its putative receptor, toll‐like receptor 9 (TLR9). Experimental Approach We hypothesized that mtDNA can be internalized in cardiomyocytes and induce an inflammatory response. Adult mouse cardiomyocytes were exposed to hypoxia‐reoxygenation and extracellular DNA. Microscale thermophoresis was used to demonstrate binding between nucleolin and DNA. Key results Expression of the pro‐inflammatory cytokines IL‐1β and TNFα were upregulated by mtDNA, but not by nuclear DNA (nDNA), in cardiomyocytes exposed to hypoxia‐reoxygenation. Blocking the RNA/DNA binding protein nucleolin with midkine reduced expression of IL‐1β/TNFα and the nucleolin inhibitor AS1411 reduced interleukin‐6 release in adult mouse cardiomyocytes. mtDNA bound 10‐fold stronger than nDNA to nucleolin. In HEK293‐NF‐κB reporter cells, mtDNA induced NF‐κB activity in normoxia, while CpG‐DNA and hypoxia‐reoxygenation, synergistically induced TLR9‐dependent NF‐κB activity. Protein expression of nucleolin was found in the plasma membrane of cardiomyocytes and inhibition of nucleolin with midkine inhibited cellular uptake of CpG‐DNA. Inhibition of endocytosis did not reduce CpG‐DNA uptake in cardiomyocytes. Conclusion and implications mtDNA, but not nDNA, induce an inflammatory response in mouse cardiomyocytes during hypoxia‐reoxygenation. In cardiomyocytes, nucleolin is expressed on the membrane and blocking nucleolin reduce inflammation. Nucleolin might be a therapeutic target to prevent uptake of immunogenic DNA and reduce inflammation.
dc.languageEN
dc.rightsAttribution-NonCommercial 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by-nc/4.0/
dc.titleInhibiting nucleolin reduces inflammation induced by mitochondrial DNA in cardiomyocytes exposed to hypoxia and reoxygenation
dc.typeJournal article
dc.creator.authorMariero, Lars Henrik
dc.creator.authorTorp, May-Kristin
dc.creator.authorHeiestad, Christina Mathisen
dc.creator.authorBaysa, Anton
dc.creator.authorLi, Yuchuan
dc.creator.authorValen, Guro
dc.creator.authorVaage, Ingvar Jarle
dc.creator.authorStensløkken, Kåre-Olav
cristin.unitcode185,51,12,0
cristin.unitnameAvdeling for molekylærmedisin
cristin.ispublishedtrue
cristin.fulltextpostprint
cristin.qualitycode2
dc.identifier.cristin1764098
dc.identifier.bibliographiccitationinfo:ofi/fmt:kev:mtx:ctx&ctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=British Journal of Pharmacology&rft.volume=&rft.spage=1&rft.date=2019
dc.identifier.jtitleBritish Journal of Pharmacology
dc.identifier.volume176
dc.identifier.issue22
dc.identifier.startpage4360
dc.identifier.endpage4372
dc.identifier.doihttps://doi.org/10.1111/bph.14830
dc.identifier.urnURN:NBN:no-79198
dc.type.documentTidsskriftartikkel
dc.type.peerreviewedPeer reviewed
dc.source.issn0007-1188
dc.identifier.fulltextFulltext https://www.duo.uio.no/bitstream/handle/10852/76090/5/bph.14830.pdf
dc.type.versionPublishedVersion


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