iNOS/NO signaling regulates apoptosis induced by glycochenodeoxycholate in hepatocytes |
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Authors: | Wang Kewei Brems John J Gamelli Richard L Holterman Ai-Xuan |
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Institution: | a Departments of Pediatrics and Surgery/Section of Pediatric Surgery, Rush University Medical Center, Chicago, IL 60612, United Statesb Department of Surgery, Loyola University Medical Center, Maywood, IL 60153, United States |
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Abstract: | Inducible nitric oxide synthase (iNOS) and nitric oxide (NO) can ameliorate apoptosis induced by toxic glycochenodeoxycholate (GCDC) in hepatocytes. However, the underlying molecular mechanisms are not yet understood in detail. This study is to clarify the function of iNOS/NO and its mechanisms during the apoptotic process. The apoptosis was brought about by GCDC in rat primary hepatocytes. iNOS/NO signaling was then investigated. iNOS inhibitor 1400 W enhanced the GCDC-induced apoptosis as reflected by caspase-3 activity and TUNEL assay. Exogenous NO regulated the apoptosis subsequent to NO donor S-nitroso-N-acetyl-penicillamine (SNAP) or sodium nitroprusside (SNP). The GCDC-induced apoptosis was decreased with 0.1 mM SNAP or 0.15 mM SNP, while it was increased with 0.8 mM SNAP or 1.2 mM SNP. The endogenous iNOS inhibited apoptosis, but the exogenous NO played a dual role during the GCDC-induced apoptosis. There was a potential iNOS/Akt/survivin axis that inhibited the hepatocyte apoptosis in low doses of NO donors. In contrast, high doses of NO donors activated CHOP through p38MAP-kinase (p38MAPK), upregulated TRAIL receptor DR5, and suppressed survivin. Consequently the high doses of NO donors promoted the apoptosis in hepatocytes. Our data suggest that the iNOS/NO signaling can modulate Akt/survivin and p38MAPK/CHOP pathways to mediate the GCDC-induced the apoptosis in hepatocytes. These signaling pathways may serve as targets for therapeutic intervention in cholestatic liver disease. |
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Keywords: | iNOS inducible nitric oxide synthase NO nitric oxide GCDC glycochenodeoxycholate SNAP S-nitroso-N-acetyl-penicillamine SNP sodium nitroprusside PI3K Phosphoinositide 3-kinase NF-κB nuclear factor kappaB p38MAPK P38 mitogen-activated protein kinases CHOP CCAAT/enhancer-binding protein homologous protein TRAIL TNF-related apoptosis-inducing ligand |
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