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Influence of caveolin on constitutively activated recombinant eNOS: insights into eNOS dysfunction in BDL rat liver
H Hendrickson1, S Chatterjee, S Cao
1Department of Physiology, Mayo Clinic, Rochester, MN 55905, USA.
Summary
Portal hypertension involves reduced nitric oxide (NO) production. Activating endothelial nitric oxide synthase (eNOS) in normal livers improved NO, but not in cirrhotic livers due to caveolin interference.
Area of Science:
- Hepatology
- Vascular Biology
- Molecular Medicine
Background:
- Portal hypertension is characterized by hepatic vasoconstriction.
- Reduced endothelial nitric oxide (NO) synthase (eNOS)-derived NO contributes to this vasoconstriction.
- Understanding the mechanisms of eNOS dysfunction in liver disease is crucial.
Purpose of the Study:
- To investigate the mechanism of eNOS dysfunction in portal hypertension.
- To test the effect of a constitutively active eNOS (S1179DeNOS) in normal and cirrhotic rat livers.
- To examine the role of caveolin in eNOS dysfunction in the cirrhotic liver.
Main Methods:
- Adenoviral vectors encoding S1179DeNOS or GFP were used for gene transfer in vitro and in vivo.
- Studies were conducted in primary and propagated liver cells, and in sham and bile duct ligated (BDL) rat models.
- Immunogold electron microscopy and co-immunoprecipitation assays were used to analyze protein interactions.
Main Results:
- S1179DeNOS enhanced NO generation in normal liver cells.
- In sham rats, S1179DeNOS reduced the pressor response to methoxamine.
- In BDL rats, S1179DeNOS did not improve vasodilation, and caveolin was found to inhibit S1179DeNOS activity in hepatic stellate cells.
Conclusions:
- Active eNOS functions properly in normal liver but is dysfunctional in the cirrhotic liver.
- Caveolin expression and binding to eNOS in BDL nonparenchymal cells, including hepatic stellate cells, likely accounts for this dysfunction.
- Targeting caveolin may be a therapeutic strategy for portal hypertension.
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