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Gastroenterology. 2003 Aug;125(2):522-31.

Transduction of the liver with activated Akt normalizes portal pressure in cirrhotic rats.

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  • 1Hormonal Laboratory, Hospital Clnic Universitari, Villarroel 170, Barcelona 08036, Spain. mmorales@medicina.ub.es

Abstract

BACKGROUND & AIMS:

Portal hypertension in cirrhosis is secondary to an increase in hepatic resistance that occurs mainly through collagen deposition. However, recent evidence points to a major contribution by other factors, such as an intrahepatic reduction in nitric oxide production. Akt is a major activator of the endothelial nitric oxide synthase (eNOS) enzyme, but its potential role in intrahepatic resistance in cirrhosis is unknown. For this reason the aims of the present study were to determine whether there is an impaired Akt activation in cirrhotic livers and how this phenomenon relates to the decrease in NO production associated with portal hypertension.

METHODS:

Cirrhosis was induced in rats by carbon tetrachloride inhalation. Protein abundance and phosphorylation status of Akt and eNOS were examined by Western blotting. The role of Akt in the liver of cirrhotic rats was investigated through infection with adenoviruses encoding either beta-galactosidase (beta-gal) or constitutively active Akt (myr-Akt).

RESULTS:

The liver of cirrhotic animals showed a significant reduction in Akt and eNOS phosphorylation. Adenoviral delivery of myr-Akt restored eNOS phosphorylation and increased the intrahepatic concentration of guanosine 3',5'-cyclic monophosphate. These events were associated with normalization in portal pressure and a significant increase in mean arterial pressure after 3 days of adenoviral infection. In contrast, transduction of livers with beta-gal did not produce any change in these hemodynamic parameters.

CONCLUSIONS:

myr-Akt gene therapy restored Akt activation and NO production in the cirrhotic liver, suggesting that this therapy may be useful for the treatment of portal hypertension.

PMID:
12891555
[PubMed - indexed for MEDLINE]
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