Heart-specific NFAT5 knockout suppresses type I interferon signaling and aggravates coxsackievirus-induced myocarditis.

Autor: Zhao G; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.; Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada., Zhang HM; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.; Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada., Nasseri AR; Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada., Yip F; Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada., Telkar N; British Columbia Cancer Research Centre, University of British Columbia, Vancouver, Canada.; British Columbia Children's Hospital Research Institute, Vancouver, Canada., Chen YT; Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada., Aghakeshmiri S; Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada., Küper C; MSH Medical School Hamburg, IMM Institute for Molecular Medicine, Medical University, Hamburg, Germany., Lam W; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.; British Columbia Cancer Research Centre, University of British Columbia, Vancouver, Canada., Yang W; Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA., Zhao J; Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada., Luo H; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada. honglin.luo@hli.ubc.ca.; Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada. honglin.luo@hli.ubc.ca., McManus BM; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada. bruce.mcmanus@hli.ubc.ca.; Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada. bruce.mcmanus@hli.ubc.ca., Yang D; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada. decheng.yang@hli.ubc.ca.; Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, 1081 Burrard Street, Vancouver, B.C, V6Z 1Y6, Canada. decheng.yang@hli.ubc.ca.
Jazyk: angličtina
Zdroj: Basic research in cardiology [Basic Res Cardiol] 2024 Dec; Vol. 119 (6), pp. 1075-1092. Date of Electronic Publication: 2024 Jun 05.
DOI: 10.1007/s00395-024-01058-w
Abstrakt: Nuclear factor of activated T cells 5 (NFAT5) is an osmosensitive transcription factor that is well-studied in renal but rarely explored in cardiac diseases. Although the association of Coxsackievirus B3 (CVB3) with viral myocarditis is well-established, the role of NFAT5 in this disease remains largely unexplored. Previous research has demonstrated that NFAT5 restricts CVB3 replication yet is susceptible to cleavage by CVB3 proteases. Using an inducible cardiac-specific Nfat5-knockout mouse model, we uncovered that NFAT5-deficiency exacerbates cardiac pathology, worsens cardiac function, elevates viral load, and reduces survival rates. RNA-seq analysis of CVB3-infected mouse hearts revealed the significant impact of NFAT5-deficiency on gene pathways associated with cytokine signaling and inflammation. Subsequent in vitro and in vivo investigation validated the disruption of the cytokine signaling pathway in response to CVB3 infection, evidenced by reduced expression of key cytokines such as interferon β1 (IFNβ1), C-X-C motif chemokine ligand 10 (CXCL10), interleukin 6 (IL6), among others. Furthermore, NFAT5-deficiency hindered the formation of stress granules, leading to a reduction of important stress granule components, including plakophilin-2, a pivotal protein within the intercalated disc, thereby impacting cardiomyocyte structure and function. These findings unveil a novel mechanism by which NFAT5 inhibits CVB3 replication and pathogenesis through the promotion of antiviral type I interferon signaling and the formation of cytoplasmic stress granules, collectively identifying NFAT5 as a new cardio protective protein.
Competing Interests: Declarations. Conflict of interest: The authors declare no conflicts of interest. Ethical approval: All animal protocols were approved by, and performed in accordance with, the Animal Care Committee of Faculty of Medicine, University of British Columbia (protocol number A20-0065).
(© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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