Heme oxygenase attenuates oxidative stress and inflammation, and increases VEGF expression in portal hypertensive rats.
OBJECTIVE
The pathophysiological significance of heme oxygenase-1 up-regulation in portal hypertension is not completely understood. In this study, we determined the role of heme oxygenase-1 on oxidative stress, inflammation, angiogenesis, and splanchnic hemodynamics in rats with portal hypertension induced by partial portal vein ligation.


METHODS
Rats were treated with the heme oxygenase inhibitor SnMP or vehicle for 7 days. Then, oxidative stress was quantified by superoxide anion production, and inflammatory response was assessed by immunofluorescence. Expression of angiogenesis mediators was determined by western blotting, and the extent of portosystemic collaterals by radioactive microspheres. Hemodynamic studies were performed by flowmetry.


RESULTS
Oxidative stress was significantly increased in the mesentery of portal hypertensive rats, as compared with sham-operated controls. In portal hypertensive rats, chronic heme oxygenase inhibition (1) potentiated oxidative stress and inflammation, (2) significantly decreased VEGF expression, without modifying the extent of collaterals or the splanchnic neovascularization, and (3) significantly decreased superior mesenteric artery blood flow and portal pressure.


CONCLUSIONS
This study demonstrates that heme oxygenase plays an important (beneficial) role attenuating oxidative stress and inflammation, but it also plays a detrimental role in stimulating VEGF production, and contributing to the development of hyperdynamic splanchnic circulation in rats with portal hypertension.
Angermayr
Bernhard
B
Liver Unit, Hepatic Hemodynamic Laboratory, Institut d'Investigacions Biomediques August Pi i Sunyer, Hospital Clinic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain.
Mejias
Marc
M
Gracia-Sancho
Jorge
J
Garcia-Pagan
Juan Carlos
JC
Bosch
Jaime
J
Fernandez
Mercedes
M
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D006975:Hypertension, Portal / Q000201:enzymology*; D007249:Inflammation / Q000201:enzymology*; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008665:Metalloporphyrins; D011524:Protoporphyrins; D042461:Vascular Endothelial Growth Factor A; C032628:tin protoporphyrin IX; D051547:Heme Oxygenase-1