Hepatocellular iNOS protects liver from ischemia/reperfusion injury through HSF1-dependent activation of HSP70.

Abstract

Although the role of inducible nitric oxide synthase (iNOS) in hepatic ischemia/reperfusion (I/R) injury remains controversial and confusing, with both harmful and beneficial effects in animal studies, the mechanism of these incongruous actions remains unclear. In the current study, we generated bone marrow chimeric mice with hepatocyte-restricted expression of iNOS. Chimeric mice and primary hepatocytes were subjected to I/R or anoxia/reoxygenation stimulation, respectively. The role of iNOS in liver I/R injury and the underlying molecular mechanisms were investigated. Hepatocyte-derived iNOS resulted in hepatoprotection from I/R injury, as well as in vitro experiments. Mechanistically, iNOS upregulates Heat shock protein (HSP) 70 by augmenting heat shock factor 1 (HSF1) binding to the HSP70 gene promoter. Importantly, inhibition of HSP70 partly reversed the iNOS overexpression-mediated hepatoprotection. The present findings demonstrate that hepatocellular iNOS protects from hepatic I/R injury through the HSF1-dependent activation of the HSP70. The upregulation of hepatocellular iNOS may offer a promising strategy for protecting against I/R injury.

• Authors: Yingli Qiao, Xueli Zhang, Guimei Zhao, Zhiheng Liu, Mingyong Yu, Zheping Fang, Xuehua Li
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 512 Issue 4 Pg. 882-888 (05 14 2019) ISSN: 1090-2104 [Electronic] United States
• PMID: 30929917 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• HSP70 Heat-Shock Proteins
• Heat Shock Transcription Factors
• Hsf1 protein, mouse
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse

Topics

• Animals
• HSP70 Heat-Shock Proteins (genetics, metabolism)
• Heat Shock Transcription Factors (metabolism)
• Hepatocytes (metabolism, pathology)
• Liver (blood supply, physiopathology)
• Mice, Inbred C57BL
• Mice, Knockout
• Nitric Oxide Synthase Type II (genetics, metabolism)
• Promoter Regions, Genetic
• Reperfusion Injury (genetics, metabolism, pathology)
• Up-Regulation