Endotoxin causes up-regulation of endothelin receptors in cultured hepatic stellate cells via nitric oxide-dependent and -independent mechanisms.
Hepatic stellate cells (HSC) and their transformed phenotype found in the chronically injured liver play important roles in hepatic physiology and pathology. HSC produce and react to a potent contractile peptide endothelin-1 (ET-1) and also synthesize a vasorelaxant nitric oxide (NO) upon stimulation with endotoxin. However, whether endotoxin affects ET-1 system of HSC and if this is a mechanism of endotoxin-induced hepatic injury is not known. We characterized synthesis of ET-1 and NO and ET-1 receptors in cultured quiescent and transformed HSC subjected to endotoxin treatment. Endotoxin (1 - 1000 ng ml(-1)) stimulated synthesis of ET-1 and NO and up-regulated ET-1 receptors in both cell types. Inhibition of NO synthesis by N(G)-monomethyl-L-homoarginine strongly inhibited endotoxin-induced increase in ET-1 receptors in transformed HSC but produced small additional increase in quiescent HSC. Inhibition of soluble guanylyl cyclase by 1H-[1,2, 4]oxadiazolo[4,3-a]quinoxalin-1-one blocked the effect of endotoxin on ET-1 receptors in both cell types. Moreover, ET-1 receptors were increased in both cell types during earlier time points (1 - 4 h) of endotoxin treatment in the absence of the stimulation of NO synthesis. These results demonstrate that endotoxin up-regulates ET-1 receptors in HSC by NO-dependent and -independent mechanisms. Such effects of endotoxin can be of importance in acute endotoxemia and during chronic injury of the liver.
Gandhi
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Department of Surgery, University of Pittsburgh, E-1540 BST, 200 Lothrop Street, Pittsburgh, Pennsylvania, PA 15213, USA. Gandhics@msx.upmc.edu
Uemura
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Kuddus
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D000818:Animals; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D004731:Endotoxins / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D009573:Nitrites / Q000378:metabolism; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004731:Endotoxins; D008070:Lipopolysaccharides; D009573:Nitrites; D010069:Oxadiazoles; D011810:Quinoxalines; D017466:Receptors, Endothelin; D009569:Nitric Oxide