Adeno-associated virus-mediated heme oxygenase-1 gene transfer suppresses the progression of micronodular cirrhosis in rats.
OBJECTIVE
To test the hypothesis that enhancement of the activity of heme oxygenase can interfere with processes of fibrogenesis associated with recurrent liver injury, we investigated the therapeutic potential of over-expression of heme oxygense-1 in a CCl(4)-induced micronodular cirrhosis model.


METHODS
Recombinant adeno-associated viruses carrying rat HO-1 or GFP gene were generated. 1x 10(12) vg of adeno-associated viruses were administered through portal injection at the time of the induction of liver fibrosis.


RESULTS
Conditioning the rat liver with over-expression of HO-1 by rAAV/HO-1 significantly increased the HO enzymatic activities in a stable manner. The development of micronodular cirrhosis was significantly inhibited in rAAV/HO-1-transduced animals as compared to controls. Portal hypertension was markedly diminished in rAAV/HO-1-transduced animals as compared to controls, whereas there are no significant changes in systolic blood pressure. This finding was accompanied with improved liver biochemistry, less infiltrating macrophages and less activated hepatic stellate cells (HSCs) in rAAV/HO-1-transduced livers.


CONCLUSIONS
Enhancement of HO activity in the livers suppresses the development of cirrhosis.
Tsui
Tung-Yu
TY
Department of Surgery, Center for the Study of Liver Disease, the University of Hong Kong, Pokfulam, Hong Kong. tung-yu.tsui@klinik.uni-regensburg.de
Lau
Chi-Keung
CK
Ma
Jian
J
Glockzin
Gabriel
G
Obed
Aiman
A
Schlitt
Hans-J
HJ
Fan
Sheung-Tat
ST
D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D000229:Dependovirus / Q000235:genetics*; D022761:Gene Transfer, Horizontal; D015316:Genetic Therapy; D051547:Heme Oxygenase-1 / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology / Q000628:therapy*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D002251:Carbon Tetrachloride; D051547:Heme Oxygenase-1