Carbon monoxide protects against hepatic ischemia/reperfusion injury via ROS-dependent Akt signaling and inhibition of glycogen synthase kinase 3β.

Abstract

Carbon monoxide (CO) may exert important roles in physiological and pathophysiological states through the regulation of cellular signaling pathways. CO can protect organ tissues from ischemia/reperfusion (I/R) injury by modulating intracellular redox status and by inhibiting inflammatory, apoptotic, and proliferative responses. However, the cellular mechanisms underlying the protective effects of CO in organ I/R injury remain incompletely understood. In this study, a murine model of hepatic warm I/R injury was employed to assess the role of glycogen synthase kinase-3 (GSK3) and phosphatidylinositol 3-kinase (PI3K)-dependent signaling pathways in the protective effects of CO against inflammation and injury. Inhibition of GSK3 through the PI3K/Akt pathway played a crucial role in CO-mediated protection. CO treatment increased the phosphorylation of Akt and GSK3-beta (GSK3β) in the liver after I/R injury. Furthermore, administration of LY294002, an inhibitor of PI3K, compromised the protective effect of CO and decreased the level of phospho-GSK3β after I/R injury. These results suggest that CO protects against liver damage by maintaining GSK3β phosphorylation, which may be mediated by the PI3K/Akt signaling pathway. Our study provides additional support for the therapeutic potential of CO in organ injury and identifies GSK3β as a therapeutic target for CO in the amelioration of hepatic injury.

• Authors: Hyo Jeong Kim, Yeonsoo Joe, Jin Sun Kong, Sun-Oh Jeong, Gyeong Jae Cho, Stefan W Ryter, Hun Taeg Chung
• Journal: Oxidative medicine and cellular longevity (Oxid Med Cell Longev) Vol. 2013 Pg. 306421 ( 2013) ISSN: 1942-0994 [Electronic] United States
• PMID: 24454979 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclic AMP Response Element-Binding Protein
• Lipopolysaccharides
• Membrane Proteins
• Pag1 protein, mouse
• Phosphoinositide-3 Kinase Inhibitors
• Phosphoproteins
• Protective Agents
• Reactive Oxygen Species
• Transcription Factor RelA
• Interleukin-10
• Carbon Monoxide
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Gsk3b protein, mouse
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3

Topics

• Administration, Inhalation
• Animals
• Carbon Monoxide (administration & dosage, pharmacology, therapeutic use)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Enzyme Activation (drug effects)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, metabolism)
• Glycogen Synthase Kinase 3 beta
• Hep G2 Cells
• Humans
• Inflammation (pathology)
• Interleukin-10 (biosynthesis)
• Lipopolysaccharides (pharmacology)
• Liver (blood supply, drug effects, enzymology, pathology)
• Male
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred C57BL
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphoproteins (metabolism)
• Protective Agents (administration & dosage, pharmacology, therapeutic use)
• Proto-Oncogene Proteins c-akt (metabolism)
• Reactive Oxygen Species (metabolism)
• Reperfusion Injury (drug therapy, enzymology, pathology)
• Signal Transduction (drug effects)
• Transcription Factor RelA (metabolism)