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

Hyo Jeong Kim; Yeonsoo Joe; Jin Sun Kong; Sun-Oh Jeong; Gyeong Jae Cho; Stefan W Ryter; Hun Taeg Chung

doi:10.1155/2013/306421

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

Oxid Med Cell Longev. 2013:2013:306421. doi: 10.1155/2013/306421. Epub 2013 Dec 18.

Authors

Hyo Jeong Kim¹, Yeonsoo Joe¹, Jin Sun Kong¹, Sun-Oh Jeong¹, Gyeong Jae Cho², Stefan W Ryter³, Hun Taeg Chung¹

Affiliations

¹ School of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
² Department of Anatomy, School of Medicine, and Institute of Health Sciences, Gyeongsang National University, Jinju 660-701, Republic of Korea.
³ Department of Medicine, Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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