Increased oxidative stress in cirrhotic rat livers: A potential mechanism contributing to reduced nitric oxide bioavailability
✍ Scribed by Jorge Gracia-Sancho; Bàrbara Laviña; Aina Rodríguez-Vilarrupla; Héctor García-Calderó; Mercedes Fernández; Jaume Bosch; Joan-Carles García-Pagán
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 612 KB
- Volume
- 47
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
In cirrhotic livers, decreased nitric oxide (NO) bioavailability is a major factor increasing intrahepatic vascular tone. In several vascular disorders, an increase in superoxide (O 2 ؊ ) has been shown to contribute to reduced NO bioavailability through its reaction with NO to form peroxynitrite. This study was aimed to test the hypothesis that, in cirrhotic livers, increased O 2 ؊ , by reacting with NO, reduces NO bioavailability. In control and cirrhotic rat livers, NO bioavailability was evaluated by the measurement of cyclic guanosine monophosphate in liver tissue and by 4-amino-5-methylamino-2,7-difluorofluorescein diacetate (DAF-FM-DA) fluorescence in isolated sinusoidal endothelial cells (SEC); the O 2 ؊ content was determined by dihydroethidium staining in fresh liver sections. In addition, the role of endothelial nitric oxide synthase (eNOS), xanthine oxidase (XO), and cyclooxygenase (COX) as possible sources of O 2 ؊ and the role of superoxide dismutase (SOD) enzymatic activity as an O 2 ؊ scavenger were determined in liver homogenates. Protein-nitrotyrosination, a marker of the NO-O 2 ؊ reaction, was evaluated in liver homogenates. Furthermore, in control SEC and bovine aortic endothelial cells, NO modulation by O 2 ؊ was evaluated. Cirrhotic livers exhibited increased O 2 ؊ levels. This was due, at least in part, to increased production by COX and XO but not eNOS and to reduced scavenging by SOD. Increased O 2 ؊ was associated with a significant reduction in NO bioavailability and increased nitrotyrosinated proteins. In endothelial cells, an inverse relationship between O 2 ؊ levels and NO bioavailability was observed. Conclusion: Our data show that oxidative stress may contribute to reduced NO bioavailability in cirrhotic livers, supporting the evaluation of O 2 ؊ reduction as a potential mechanism to restore NO content.