Posttranslational activation of endothelial nitric oxide synthase attenuates carbon tetrachloride-induced hepatotoxicity in newborn rats.
Nitric Oxide (NO) can be cytotoxic or cytoprotective depending on amount and location of its generation. eNOS is important in modulating blood flow and is allosterically regulated. Inducible NOS (iNOS) tends to produce large quantities of NO leading to cell injury. We studied the role and regulation of NOS in carbon tetrachloride (CCl(4))-induced hepatotoxicity in newborn rats. eNOS was expressed before birth, significantly increased on day of life (DOL) 2 reaching a maximum at DOL-20. iNOS was absent at all ages. CCl(4) treatment resulted in hepatic injury in newborn rats and damage was intensified by co-administration of a general NOS inhibitor. CCl(4) treatment increased eNOS activity without change in mRNA or protein levels. Administration of CCl(4) resulted in an increase in phosphorylation of threonine protein kinase (Akt) and eNOS, associated with an increase in eNOS activity. Administration of wortmannin (phosphatidylinositol 3-kinase, PI3 K, inhibitor) attenuated the phosphorylation of Akt and eNOS and reduced eNOS activity. Co-administration of CCl(4) and wortmannin potentiated the degree of hepatic injury. iNOS was not detectable in CCl(4)-treated rats. This data indicates a protective role for eNOS in CCl(4)-induced hepatotoxicity in newborn rats with protection accomplished by activation of eNOS via posttranslational modification of the PI3 K/Akt signaling pathway.
Liu
Hua
H
Department of Pediatrics, University of Mississippi Medical Center, Jackson, Mississippi 36216, USA.
Subramony
Charu
C
Nowicki
Michael
M
D000367:Age Factors; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002251:Carbon Tetrachloride; D019610:Cytoprotection; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008107:Liver Diseases / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D000077191:Wortmannin
D000730:Androstadienes; D002251:Carbon Tetrachloride; D004791:Enzyme Inhibitors; D019331:NG-Nitroarginine Methyl Ester; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat