Increased vascular heme oxygenase-1 expression contributes to arterial vasodilation in experimental cirrhosis in rats

Authors

  • Yung-Chang Chen,

    1. Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado
    2. Division of Critical Care Nephrology, Chang Gung Memorial Hospital, Taipei, Taiwan
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  • Pere Ginès,

    1. Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado
    2. Liver Unit, Institute for Digestive Diseases, Hospital Clínic, University of Barcelona, Barcelona, Spain
    3. Institut d'Investigacions Biomèdiques August Pi-Sunyer, Instituto Reina Sofia de Investigación Nefrológica, Barcelona, Catalunya, Spain
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  • Jianhui Yang,

    1. Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado
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  • Sandra N. Summer,

    1. Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado
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  • Sandor Falk,

    1. Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado
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  • Nash S. Russell,

    1. Department of Pathology, University of Colorado Health Sciences Center, Denver, Colorado
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  • Robert W. Schrier

    Corresponding author
    1. Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado
    • Division of Renal Diseases and Hypertension, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Box B173, Denver, CO 80262
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    • fax: 303-315-2685


Abstract

Vascular heme oxygenase (HO) regulates vascular tone in normal conditions and in some pathologic circumstances (e.g., sepsis). However, its possible role in the pathogenesis of arterial vasodilation in cirrhosis is unknown. To address this question, the expression and activity of HO in arterial vessels was studied in rats at 1, 2, and 4 weeks after bile duct ligation (BDL) or sham operation. A progressively increased expression of HO-1 was found in aorta and mesenteric arteries of BDL rats in a close chronologic relationship with the progression from acute cholestatic liver injury (1 week) to the fully developed cirrhosis with intense systemic arterial vasodilation (4 weeks). No changes were found in the expression of the constitutive isoform HO-2. HO-1 was mainly located in vascular smooth muscle cells of the arterial wall. Aortic HO activity increased in parallel with the expression of HO-1 (up to 600% in rats with cirrhosis compared with sham rats) and correlated with hemodynamic parameters. Increased expression of HO-1 and HO activity were also found in other organs, such as liver and spleen, though to a lesser extent compared with vascular tissue. The acute administration of an inhibitor of HO to cirrhotic rats, at a dose that normalized aortic HO activity, was associated with significantly greater effects on arterial pressure, total peripheral vascular resistance, and cardiac index, compared with effects in sham rats. In conclusion, these findings are consistent with a role for HO in the pathogenesis of arterial vasodilation in cirrhosis. (HEPATOLOGY 2004;39:1075–1087.)

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