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This Article Full Text Full Text (PDF) All Versions of this Article: 285/3/G652    most recent 00143.2003v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (9) Citing Articles via Google Scholar Google Scholar Articles by Hendrickson, H. Articles by Shah, V. Search for Related Content PubMed PubMed Citation Articles by Hendrickson, H. Articles by Shah, V.

LIVER AND BILIARY TRACT

Influence of caveolin on constitutively activated recombinant eNOS: insights into eNOS dysfunction in BDL rat liver

¹Gastrointestinal Research Unit, Department of Physiology and Tumor Biology Program, Mayo Clinic, Rochester, Minnesota 55905;²Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06510; and³Laboratorio de Hormonal, Hospital Clinic, 08036 Barcelona, Spain

Submitted 26 March 2003 ; accepted in final form 26 May 2003

Diminished endothelial nitric oxide (NO) synthase (eNOS)-derived NO production from the hepatic vascular endothelium contributes to hepatic vasoconstriction in portal hypertension. The aim of this study was to examine the mechanism of this process by testing the influence of a constitutively active form of eNOS (S1179DeNOS) in both primary and propagated liver cells in vitro and in the sham and bile duct ligated (BDL) rat liver in vivo, using an adenoviral vector encoding green fluorescent protein (AdGFP) and S1179DeNOS (AdS1179DeNOS). AdS1179DeNOS transduction augmented basal and agonist-stimulated NO generation in nonparenchymal liver cells. Sham rats transduced in vivo with AdS1179DeNOS evidenced a decreased pressor response to incremental doses of the vasoconstrictor methoxamine compared with sham rats transduced with AdGFP. However, BDL rats transduced with AdS1179DeNOS did not display improved vasodilatory responses as evidenced by similar flow-dependent pressure increases to that observed in BDL rats transduced with AdGFP, despite similar levels of viral transgene expression. We next examined the influence of the eNOS inhibitory protein caveolin on S1179DeNOS dysfunction in cirrhotic liver. Immunogold electron microscopic analysis of caveolin in BDL liver demonstrated prominent expression not only in liver endothelial cells, but also in hepatic stellate cells. In vitro studies in the LX2 hepatic stellate cell line demonstrate that caveolin precipitates recombinant S1179DeNOS in LX2 cells, that recombinant S1179DeNOS coprecipitates caveolin, and that binding is enhanced in the presence of overexpression of caveolin. Furthermore, caveolin overexpression inhibits recombinant S1179DeNOS activity. These studies indicate that recombinant S1179DeNOS protein functions appropriately in normal liver cells and tissue but evidences dysfunction in the cirrhotic rat liver and that caveolin expression and inhibition in BDL nonparenchymal cells, including hepatic stellate cells, may account for this dysfunction.

endothelial nitric oxide synthase; caveolin; bile duct ligated rat; portal hypertension; hepatic vasculature

This article has been cited by other articles:

				R. E. Perri, D. A. Langer, S. Chatterjee, S. J. Gibbons, J. Gadgil, S. Cao, G. Farrugia, and V. H. Shah Defects in cGMP-PKG pathway contribute to impaired NO-dependent responses in hepatic stellate cells upon activation Am J Physiol Gastrointest Liver Physiol, March 1, 2006; 290(3): G535 - G542. [Abstract] [Full Text] [PDF]