Adenovirus-mediated hepatocyte growth factor gene transfer prevents lethal liver failure in rats.
Hepatocyte growth factor (HGF) has a potent antiapoptotic effect on hepatocytes in D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-treated rats. Here, we report that adenovirus mediated HGF gene transfer into liver prevents liver failure and reduces mortality of rats treated with d-GalN/LPS. Fisher 344 rats, which were given intraperitoneal injections of pAxCAHGF 48 h before, were treated with D-GalN/LPS. Serum ALT in the HGF group at 6 and 12 h after D-GalN/LPS was decreased to 1/6 and 1/12 of the control group (P < 0.01, each). Concomitant reduction of apoptotic cells were also observed. The Kaplan-Meier analysis showed that a survival rate in the HGF group was improved, compared to that in the control group (P < 0.05). Caspase-3 activity in the HGF group decreased, compared to that in the control group, especially at 12 h (P < 0.05), although it maintained a high level in the control group. Expression of Bcl-xL and cyclooxygenase-2 (Cox-2) was induced in liver by HGF gene transfer. These data suggest that HGF exerts an antiapoptotic effect through dual induction of Bcl-xL and Cox-2, which suppresses caspase-3 activity.
Nomi
T
T
Second Department of Internal Medicine, Tottori University, Yonago, 683-8504, Japan.
Shiota
G
G
Isono
M
M
Sato
K
K
Kawasaki
H
H
D000256:Adenoviridae / Q000235:genetics*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001483:Base Sequence; D053148:Caspase 3; D020169:Caspases / Q000235:genetics; D017931:DNA Primers; D018014:Gene Transfer Techniques; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D017093:Liver Failure / Q000628:therapy*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D014162:Transfection
D017931:DNA Primers; D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor; D000410:Alanine Transaminase; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases