title: Superoxide dismutase gene transfer reduces portal pressure in CCl4 cirrhotic rats with portal hypertension.
abstract: BACKGROUND
  Increased intrahepatic vascular tone in cirrhosis has been attributed to a decrease of hepatic nitric oxide (NO) secondary to disturbances in the post-translational regulation of the enzyme eNOS. NO scavenging by superoxide (O(2)(-)) further contributes to a reduction of NO bioavailability in cirrhotic livers.
  
  
  OBJECTIVE
  To investigate whether removing increased O(2)(-) levels could be a new therapeutic strategy to increase intrahepatic NO, improve endothelial dysfunction and reduce portal pressure in cirrhotic rats with portal hypertension.
  
  
  METHODS
  Adenoviral vectors expressing extracellular superoxide dismutase (SOD) (AdECSOD) or beta-galactosidase (Adbetagal) were injected intravenously in control and CCl(4)-induced cirrhotic rats. After 3 days, liver O(2)(-) levels were determined by dihydroethidium staining, NO bioavailability by hepatic cGMP levels, nitrotyrosinated proteins by immunohistochemistry and western blot, and endothelial function by responses to acetylcholine in perfused rat livers. Mean arterial pressure (MAP) and portal pressure were evaluated in vivo.
  
  
  RESULTS
  Transfection of cirrhotic livers with AdECSOD produced a significant reduction in O(2)(-) levels, a significant increase in hepatic cGMP, and a decrease in liver nitrotyrosinated proteins which were associated with a significant improvement in the endothelium-dependent vasodilatation to acetylcholine. In addition, in cirrhotic livers AdECSOD transfection produced a significant reduction in portal pressure (17.3 (SD 2) mm Hg vs 15 (SD 1.6) mm Hg; p<0.05) without significant changes in MAP. In control rats, AdECSOD transfection prevents the increase in portal perfusion pressure promoted by an ROS-generating system.
  
  
  CONCLUSIONS
  In cirrhotic rats, reduction of O(2)(-) by AdECSOD increases NO bioavailability, improves intrahepatic endothelial function and reduces portal pressure. These findings suggest that scavenging of O(2)(-) might be a new therapeutic strategy in the management of portal hypertension.
authors.affiliation: Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic, Barcelona, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Laviña
authors.forename: J
authors.initials: J
authors.lastname: Gracia-Sancho
authors.forename: A
authors.initials: A
authors.lastname: Rodríguez-Vilarrupla
authors.forename: Y
authors.initials: Y
authors.lastname: Chu
authors.forename: D D
authors.initials: DD
authors.lastname: Heistad
authors.forename: J
authors.initials: J
authors.lastname: Bosch
authors.forename: J C
authors.initials: JC
authors.lastname: García-Pagán
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002251:Carbon Tetrachloride; D004730:Endothelium, Vascular / Q000503:physiopathology; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006975:Hypertension, Portal / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D008102:Liver Circulation; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D010101:Oxygen Consumption; D017082:Portal Pressure; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism
chemical_list: D009569:Nitric Oxide; D002251:Carbon Tetrachloride; D013482:Superoxide Dismutase