Opposite regulation of endothelial NO synthase by HSP90 and caveolin in liver and lungs of rats with hepatopulmonary syndrome.
The hepatopulmonary syndrome is a complication of cirrhosis that associates an overproduction of nitric oxide (NO) in lungs and a NO defect in the liver. Because endothelial NO synthase (eNOS) is regulated by caveolin that decreases and heat shock protein 90 (HSP90) that increases NO production, we hypothesized that an opposite regulation of eNOS by caveolin and HSP90 might explain the opposite NO production in both organs. Cirrhosis was induced by a chronic bile duct ligation (CBDL) performed 15, 30, and 60 days before sample collection and pharmacological tests. eNOS, caveolin, and HSP90 expression were measured in hepatic and lung tissues. Pharmacological tests to assess NO released by shear stress and by acetylcholine were performed in livers (n = 28) and lungs (n = 28) isolated from normal and CBDL rats. In lungs from CBDL rats, indirect evidence of high NO production induced by shear stress was associated with a high binding of HSP90 and a low binding of caveolin to eNOS. Opposite results were observed in livers from CBDL rats. Our study shows an opposite posttranslational regulation of eNOS by HSP90 and caveolin in lungs and liver from rats with CBDL. Such opposite posttranslational regulation of eNOS by regulatory proteins may explain in part the pulmonary overproduction of NO and the hepatic NO defect in rats with hepatopulmonary syndrome.
Frossard
Jean-Louis
JL
Laboratoire de Physiopathologie Hépatique et Imagerie Moléculaire, Hôpitaux Universitaires de Genève, Rue Micheli-du-Crest, 24, 1205 Geneva, Switzerland.
Schiffer
Eduardo
E
Cikirikcioglu
Banu
B
Bourquin
Joëlle
J
Morel
Denis R
DR
Pastor
Catherine M
CM
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D001649:Bile Duct Diseases / Q000503:physiopathology; D022461:Caveolins / Q000096:biosynthesis / Q000502:physiology*; D003135:Common Bile Duct; D018841:HSP90 Heat-Shock Proteins / Q000096:biosynthesis / Q000502:physiology*; D020065:Hepatopulmonary Syndrome / Q000201:enzymology / Q000503:physiopathology*; D066298:In Vitro Techniques; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008026:Ligation; D008099:Liver / Q000201:enzymology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology*; D052250:Nitric Oxide Synthase Type III / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology; D010477:Perfusion; D011651:Pulmonary Artery / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D016227:Benzoquinones; D022461:Caveolins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D052250:Nitric Oxide Synthase Type III; D000109:Acetylcholine; D009638:Norepinephrine; C001277:geldanamycin