Gene transfer of the neuronal NO synthase isoform to cirrhotic rat liver ameliorates portal hypertension.
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.
Yu
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Q
Duke Liver Center, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Shao
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R
Qian
H S
HS
George
S E
SE
Rockey
D C
DC
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D048429:Cell Size; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D019332:Endothelin-1 / Q000037:antagonists & inhibitors; D005240:Feasibility Studies; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D006975:Hypertension, Portal / Q000209:etiology / Q000628:therapy*; D007527:Isoenzymes / Q000235:genetics* / Q000502:physiology; D008106:Liver Cirrhosis, Experimental / Q000150:complications*; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000502:physiology; D052248:Nitric Oxide Synthase Type I; D009573:Nitrites / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000502:physiology
D018076:DNA, Complementary; D019332:Endothelin-1; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D009573:Nitrites; D011993:Recombinant Fusion Proteins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat