Gene transfer of the neuronal NO synthase isoform to cirrhotic rat liver ameliorates portal hypertension
Qing Yu, … , Samuel E. George, Don C. Rockey
Qing Yu, … , Samuel E. George, Don C. Rockey
Published March 15, 2000
Citation Information: J Clin Invest. 2000;105(6):741-748. https://doi.org/10.1172/JCI7997.
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Article

Gene transfer of the neuronal NO synthase isoform to cirrhotic rat liver ameliorates portal hypertension

Abstract

Reduced production of nitric oxide (NO) in the cirrhotic liver results from a defect in hepatic endothelial cell nitric oxide synthase (ecNOS) and appears to contribute to the high intrahepatic resistance and portal hypertension typical of cirrhosis. Therefore, we postulated that targeting a heterologous NOS isoform to sinusoidal endothelial cells or other perisinusoidal cells, such as hepatic stellate cells, would counter the defect in NO production and reduce resistance to blood flow. Recombinant adenovirus (Ad) carrying the neuronal NOS gene (nNOS) targeted liver sinusoidal endothelial cells, stellate cells, and hepatocytes more efficiently than the corresponding cells in cirrhotic livers, but transduction rates were substantial even in cirrhotic animals. Expression of nNOS in each liver cell type, whether from normal or injured liver, caused increased NO production and inhibited endothelin-1–induced contractility of perisinusoidal stellate cells. Finally, in 2 different in vivo models of cirrhosis and portal hypertension, transduction of livers with recombinant Ad.nNOS significantly reduced intrahepatic resistance and portal pressure. The data highlight the feasibility of gene transfer to diseased liver and hepatic cells and demonstrate the potential of a novel therapy for portal hypertension caused by cirrhosis.

Authors

Qing Yu, Rong Shao, Hu Sheng Qian, Samuel E. George, Don C. Rockey

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Effect of nNOS gene transfer on stellate cell contractility in vitro and...
Effect of nNOS gene transfer on stellate cell contractility in vitro and in vivo. In a, the effect of transduced nNOS on stellate cell contractility in vitro was determined. Stellate cells from normal livers were isolated, placed on thick collagen lattices, and allowed to undergo spontaneous activation. Cells were transduced with Ad.nNOS, and 24 hours later contraction assays were performed. In b, BDL was performed and Ad containing nNOS or β-galactosidase was administered 2 days later; stellate cells were isolated as in Methods and placed on thick collagen matrices. After adherence (for 18 hours), lattices containing cells were placed in serum-free medium, after which endothelin-1 was added at the indicated concentrations, lattices were detached, and contraction was measured for a further 24 hours. The open bars represent cells from control animals (i.e., vehicle alone); the crossed bars represent cells from rats receiving Ad.β-gal; and the filled bars depict cells from animals receiving Ad.nNOS. AP < 0.01 compared with control or Ad.β-gal (n = 3); BP < 0.001 compared with control or Ad.β-gal (n = 3).