Nitric oxide-mediated cytoprotection of hepatocytes from glucose deprivation-induced cytotoxicity: involvement of heme oxygenase-1.
Heme oxygenase-1 (HO-1) is the rate-limiting enzyme in heme catabolism, which leads to the generation of carbon monoxide (CO), biliverdin, and free iron. One of 3 mammalian HO isoforms, HO-1, is a stress-responsive protein and known to modulate such cellular functions as cytokine production, cell proliferation, and apoptosis to protect organs and tissues from acute injury. Although nitric oxide (NO)-mediated cytoprotective effects against cytotoxicity induced by glucose deprivation have been well recognized, the underlying mechanisms remain to be elucidated. Thus, we investigate the involvement of HO-1 in the cytoprotective effects of NO. Deprivation of glucose markedly reduced the viability of BNL CL.2 cells and primary rat hepatocytes. Pretreatment with NO donor, sodium nitroprusside (SNP), protected hepatocytes from glucose deprivation-induced cytotoxicity; zinc protoporphyrin (ZnPP) IX, an inhibitor of HO, was found to block the SNP-induced cytoprotection. SNP increased the induction of HO-1 protein as well as its activity in hepatocytes. A cytoprotective effect comparable to SNP was observed when the cells were transfected with HO-1 gene or preincubated with another HO-1 inducer, hemin. Additional experiments revealed the involvement of CO in the cytoprotective effect of SNP/HO-1 in BNL CL.2 cells. CO mediated cytoprotective effect through suppression of ERK MAPK activation. In conclusion, our results show that SNP protects hepatocytes from glucose deprivation-induced cytotoxicity through up-regulation of HO-1. Thus, HO-1 might be an important cellular target of NO donor with clinical implications for the prevention of acute liver injury in several pathological conditions.
Choi
Byung-Min
BM
Medicinal Resources Research Center (MRRC) and the Department of Microbiology and Immunology, Wonkwang University School of Medicine, Iksan, Chonbuk, South Korea.
Pae
Hyun-Ock
HO
Kim
Young-Myeong
YM
Chung
Hun-Taeg
HT
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002248:Carbon Monoxide / Q000494:pharmacology; D002460:Cell Line; D006152:Cyclic GMP / Q000378:metabolism; D019610:Cytoprotection; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000378:metabolism; D004198:Disease Susceptibility; D005947:Glucose / Q000172:deficiency*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006427:Hemin / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology*; D007700:Kinetics; D008565:Membrane Proteins; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection; D019014:fas Receptor / Q000378:metabolism
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D020030:Nitric Oxide Donors; D018808:Transcription Factor AP-1; D019014:fas Receptor; D009599:Nitroprusside; D009569:Nitric Oxide; D006427:Hemin; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D006152:Cyclic GMP; D005947:Glucose