Melatonin prevents hemorrhagic shock-induced liver injury in rats through an Akt-dependent HO-1 pathway.
Although melatonin treatment following trauma-hemorrhage or ischemic reperfusion prevents organs from dysfunction and injury, the precise mechanism remains unknown. This study tested whether melatonin prevents liver injury following trauma-hemorrhage involved the protein kinase B (Akt)-dependent heme oxygenase (HO)-1 pathway. After a 5-cm midline laparotomy, male rats underwent hemorrhagic shock (mean blood pressure approximately 40 mmHg for 90 min) followed by fluid resuscitation. At the onset of resuscitation, rats were treated with vehicle, melatonin (2 mg/kg), or melatonin plus phosphoinositide 3-kinase (PI3K) inhibitor wortmannin (1 mg/kg). At 2 hr after trauma-hemorrhage, the liver tissue myeloperoxidase activity, malondialdehyde, adenosine triphosphate, serum alanine aminotransferase, and aspartate aminotransferase levels were significantly increased compared with sham-operated control. Trauma-hemorrhage resulted in a significant decrease in the Akt activation in comparison with the shams (relative density, 0.526 ± 0.031 versus 1.012 ± 0.066). Administration of melatonin following trauma-hemorrhage normalized liver Akt phosphorylation (0.993 ± 0.061), further increased mammalian target of rapamycin (mTOR) activation (5.263 ± 0.338 versus 2.556 ± 0.225) and HO-1 expression (5.285 ± 0.325 versus 2.546 ± 0.262), and reduced cleaved caspase-3 levels (2.155 ± 0.297 versus 5.166 ± 0.309). Coadministration of wortmannin abolished the melatonin-mediated attenuation of the shock-induced liver injury markers. Our results collectively suggest that melatonin prevents hemorrhagic shock-induced liver injury in rats through an Akt-dependent HO-1 pathway.
Department of Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan. hsujt2813@adm.cgmh.org.tw
Jun-Te
JT
Hsu
Chia-Jung
CJ
Kuo
Tsung-Hsing
TH
Chen
Frank
F
Wang
Chun-Jun
CJ
Lin
Ta-Sen
TS
Yeh
Tsann-Long
TL
Hwang
Yi-Yin
YY
Jan
D000255:Adenosine Triphosphate / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D053148:Caspase 3 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D019610:Cytoprotection; D004195:Disease Models, Animal; D004789:Enzyme Activation; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008107:Liver Diseases / Q000201:enzymology / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012771:Shock, Hemorrhagic / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000077191:Wortmannin
D000730:Androstadienes; D016207:Cytokines; D018836:Inflammation Mediators; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D008315:Malondialdehyde; D000255:Adenosine Triphosphate; D009195:Peroxidase; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C546845:mTOR protein, rat; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C505410:Casp3 protein, rat; D053148:Caspase 3; D008550:Melatonin; D000077191:Wortmannin