Carbon monoxide protects against hepatic ischemia/reperfusion injury via ROS-dependent Akt signaling and inhibition of glycogen synthase kinase 3β.
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.
School of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
Hyo Jeong
HJ
Kim
School of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
Yeonsoo
Y
Joe
School of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
Jin Sun
JS
Kong
School of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
Sun-Oh
SO
Jeong
Department of Anatomy, School of Medicine, and Institute of Health Sciences, Gyeongsang National University, Jinju 660-701, Republic of Korea.
Gyeong Jae
GJ
Cho
Department of Medicine, Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Stefan W
SW
Ryter
School of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea.
Hun Taeg
HT
Chung
D000280:Administration, Inhalation; D000818:Animals; D002248:Carbon Monoxide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation / Q000473:pathology; D016753:Interleukin-10 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D051996:Transcription Factor RelA / Q000378:metabolism
D002248:Carbon Monoxide; D017362:Cyclic AMP Response Element-Binding Protein; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D016753:Interleukin-10; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D020011:Protective Agents; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D051996:Transcription Factor RelA; C498709:Pag1 protein, mouse; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse