Abstract
Excessive nitric oxide (NO) production and NO-mediated nitrative stress contribute to vascular dysfunction, inflammation, and tissue injury in septic shock. New therapeutic targets are urgently needed to provide better control of NO level during septic shock. In the present study, we investigated the role of HDAC6 in the regulation of NO production and nitrative stress in a mouse model of endotoxin-induced septic shock. HDAC6 deficient mice and a specific HDAC6 inhibitor were utilized in our studies. Our data clearly indicate that HDAC6 is an important mediator of NO production in macrophages. HDAC6 mediates NO production through the regulation of iNOS expression in macrophages. HDAC6 up-regulates iNOS expression in macrophages by modulating STAT1 activation and IRF-1 expression. HDAC6 inhibition potently blocked endotoxin-induced STAT1 activation and iNOS expression in macrophages. Furthermore, HDAC6 contributes to excessive NO production and nitrotyrosine level in the blood and promotes iNOS expression in the lung tissues during septic shock. Our data reveal a novel HDAC6/STAT1/iNOS pathway that mediates excessive NO production and nitrative stress in septic shock.
Document Type
Article
Publication Date
8-20-2020
Digital Object Identifier (DOI)
https://doi.org/10.3389/fimmu.2020.01893
Funding Information
This study was supported by the National Institutes of Health, National Heart, Lung, and Blood Institute grant 5R01HL137910 (JF).
Repository Citation
Wang, Yan; Wang, Ke; and Fu, Jian, "HDAC6 Mediates Macrophage iNOS Expression and Excessive Nitric Oxide Production in the Blood During Endotoxemia" (2020). Toxicology and Cancer Biology Faculty Publications. 93.
https://uknowledge.uky.edu/toxicology_facpub/93
Notes/Citation Information
Published in Frontiers in Immunology, v. 11, article 1893.
© 2020 Wang, Wang and Fu.
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