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Blockade of wnt secretion attenuates myocardial ischemia-reperfusion injury by modulating the inflammatory response

Wnt (a portmanteau of Wingless and Int-1) signaling in the adult heart is largely quiescent. However, there is accumulating evidence that it gets reactivated during the healing process after myocardial infarction (MI). We here tested the therapeutic potential of the Wnt secretion inhibitor LGK-974 o...

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Main Authors: Meyer, Sören (Author) , Li, Xue (Author) , Meyer, Carina (Author) , Voloshanenko, Oksana (Author) , Pohl, Susann (Author) , Boutros, Michael (Author) , Katus, Hugo (Author) , Frey, Norbert (Author) , Leuschner, Florian (Author)
Format: Article (Journal)
Language:English
Published: 14 October 2022
In: International journal of molecular sciences
Year: 2022, Volume: 23, Issue: 20, Pages: 1-14
ISSN:1422-0067
DOI:10.3390/ijms232012252
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/ijms232012252
Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/1422-0067/23/20/12252
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Author Notes:Ingmar Sören Meyer, Xue Li, Carina Meyer, Oksana Voloshanenko, Susann Pohl, Michael Boutros, Hugo Albert Katus, Norbert Frey and Florian Leuschner
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Summary:Wnt (a portmanteau of Wingless and Int-1) signaling in the adult heart is largely quiescent. However, there is accumulating evidence that it gets reactivated during the healing process after myocardial infarction (MI). We here tested the therapeutic potential of the Wnt secretion inhibitor LGK-974 on MI healing. Ischemia/reperfusion (I/R) injury was induced in mice and Wnt signaling was inhibited by oral administration of the porcupine inhibitor LGK-974. The transcriptome was analyzed from infarcted tissue by using RNA sequencing analysis. The inflammatory response after I/R was evaluated by flow cytometry. Heart function was assessed by echocardiography and fibrosis by Masson’s trichrome staining. Transcriptome and gene set enrichment analysis revealed a modulation of the inflammatory response upon administration of the Wnt secretion inhibitor LGK-974 following I/R. In addition, LGK-974-treated animals showed an attenuated inflammatory response and improved heart function. In an in vitro model of hypoxic cardiomyocyte and monocyte/macrophage interaction, LGK974 inhibited the activation of Wnt signaling in monocytes/macrophages and reduced their pro-inflammatory phenotype. We here show that Wnt signaling affects inflammatory processes after MI. The Wnt secretion inhibitor LGK-974 appears to be a promising compound for future immunomodulatory approaches to improve cardiac remodeling after MI.
Item Description:Gesehen am 13.12.2022
Physical Description:Online Resource
ISSN:1422-0067
DOI:10.3390/ijms232012252

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