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Nitric oxide synthase gene transfer

  • June Sung Lee
  • Vijay Shah
Conference paper

Abstract

Chronic liver diseases are often characterized by portal hypertension, an important component of which is increased intrahepatic vascular resistance. Portal hypertension in turn has profound clinical consequences, many of which are associated with substantial morbidity and mortality1. Nitric oxide (NO) modulates numerous physiological processes in the liver circulation2. The basal production of NO in the hepatic circulation is generated through the catalytic activity of the endothelial NO synthase (eNOS) isoform, localized within liver endothelial cells (LEC) and regulated through physiological stimuli including shear stress3, 4. Several recent studies suggest that the biological activity of hepatic eNOS is diminished in portal hypertension3, 5, 6. Thus, NO supplementation is a rational therapeutic approach in portal hypertension. While NO donor therapy in portal hypertension may be beneficial under specific clinical circumstances, its benefits are limited by several factors including short half-life, high reactivity, tolerance and, most importantly, the unwanted systemic delivery of these compounds that tends to exacerbate an existing hyperdynamic circulatory state and create untoward side-effects and limit effectiveness of clinical application 7, 8.

Keywords

Portal Hypertension Hepatic Stellate Cell Adenoviral Vector Portal Pressure Bile Duct Ligation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Bosch J, Abraldes J, Groszmann R. Current management of portal hypertension. J Hepatol. 2003;38 (Suppl. 1):S54–68.Google Scholar
  2. 2.
    Clemens M. Nitric oxide in liver injury. Hepatology. 1999;30:1–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Rockey, DC, Chung JJ. Reduced nitric oxide production by endothelial cells in cirrhotic rat liver: endothelial dysfunction in portal hypertension. Gastroenterology. 1998;114:344–51.PubMedCrossRefGoogle Scholar
  4. 4.
    Shah V, Cadelina G, Seesa WC, Groszmann RI. Comparison of eNOS protein levels in SEC from normal and cirrhotic rats. Hepatology. 1997;26:359A.Google Scholar
  5. 5.
    Shah V, Toruner M, Haddad F et al. Impaired endothelial nitric oxide synthase activity associated with enhanced caveolin binding in experimental liver cirrhosis. Gastroenterology. 1999;117:1222–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Gupta T, Toruner M, Chung M, Groszmann R. Endothelial dysfunction and decreased production of nitric oxide in the intrahepatic microcirculation of cirrhotic rats. Hepatology. 1998;28:926–31.PubMedCrossRefGoogle Scholar
  7. 7.
    Shah V. Cellular and molecular basis of portal hypertension. Clin Liver Dis Portal Hypertens. 2001;5:629–44.CrossRefGoogle Scholar
  8. 8.
    Rockey D, Shah V. Nitric oxide and the liver. Hepatology. 2004;39:250–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Anderson W. Human gene therapy. Nature. 1998;392:25–30.PubMedCrossRefGoogle Scholar
  10. 10.
    Van de Casteele M, Omasta A, Janssens S et al. In vivo gene transfer of endothelial nitric oxide synthase decreases portal pressure in anaesthetised carbon tetrachloride cirrhotic rats. Gut. 2002;51:440–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Yu Q, Shao R, Zian H, George S, Rockey D. Gene transfer of the neuronal NO synthase isoform to cirrhotic rat liver ameliorates portal hypertension. J Clin Invest. 2000;105:741–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Hendrickson H, Chatterjee S, Cao S et al. Influence of caveolin on a constitutively activated form of recombinant eNOS: insights into eNOS dysfunction in the bile duct ligated rat liver. Am J Gastroenterol. 2003;285:G652–60.Google Scholar
  13. 13.
    Shah V, Chen A, Cao S et al. Gene transfer of recombinant endothelial nitric oxide synthase to liver in vivo and in vitro. Am J Physiol. 2000;279:G1023–30.Google Scholar
  14. 14.
    McCabe T, Fulton D, Roman L, Sessa W. Enhanced electron flux and reduced calmodulin dissociation may explain “calcium-independent” eNOS activation by phosphorylation. J Biol Chem. 2000;275:6123–8.PubMedCrossRefGoogle Scholar
  15. 15.
    Taimr P, Higuchi H, Kocova E, Rippe R, Friedman S, Gores G. Activated stellate cells express the TRAIL receptor-2/death receptor-5 and undergo TRAIL-mediated apoptosis. Hepatology. 2003;37:87–95.PubMedCrossRefGoogle Scholar
  16. 16.
    Fulton D, Gratton J-P, Sessa W. Post-translational control of endothelial nitric oxide synthase: why isn’t calcium/calmodulin enough? J Pharmacol Exp Ther. 2001;299:818–24.PubMedGoogle Scholar
  17. 17.
    Shah V, Hendrickson H, Cao S, Yao J, Katusic Z. Regulation of hepatic endothelial nitric oxide synthase by caveolin and calmodulin after bile duct ligation in rats. Am J Physiol. 2001;280:G1209–16.Google Scholar
  18. 18.
    Morales-Ruiz M, Cejudo-Martin P, Fernandez-Yaro G et al. Transduction of the liver with activated Akt normalizes portal pressure in cirrhotic rats. Gastroenterology. 2003; 125:522–31.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2004

Authors and Affiliations

  • June Sung Lee
  • Vijay Shah
    • 1
  1. 1.Department of Medicine, Physiology and Tumor BiologyMayo Clinic Foundation and School of MedicineRochesterUSA

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