Journal
HUMAN GENE THERAPY
Volume 20, Issue 10, Pages 1133-1142Publisher
MARY ANN LIEBERT, INC
DOI: 10.1089/hum.2009.049
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Funding
- NIH [RO1 DK062357, AI23847, AI42223]
- Dumont Research Foundation
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We have shown that overexpression of heme oxygenase-1 (HO-1) prevents the liver inflammation response leading to ischemia and reperfusion injury (IRI). This study was designed to explore the precise function and mechanism of HO-1 cytoprotection in liver IRI by employing a small interfering RNA ( siRNA) that effectively suppresses HO-1 expression both in vitro and in vivo. Using a partial lobar liver warm ischemia model, mice were injected with HO-1 siRNA/nonspecific control siRNA or Ad-HO-1/Ad-beta-gal. Those treated with HO-1 siRNA showed increased serum glutamic-oxaloacetic transaminase levels, significant liver edema, sinusoidal congestion/cytoplasmic vacuolization, and severe hepatocellular necrosis. In contrast, Ad-HO-1-pretreated animals revealed only minimal sinusoidal congestion without edema/vacuolization or necrosis. Administration of HO-1 siRNA significantly increased local neutrophil accumulation and the frequency of apoptotic cells. Mice treated with HO-1 siRNA were characterized by increased caspase-3 activity and reduced HO-1 expression, whereas those given Ad-HO-1 showed decreased caspase-3 activity and increased HO-1/Bcl-2/Bcl-xL, data confirmed by use of an in vitro cell culture system. Thus, by using an siRNA approach this study confirms that HO-1 provides potent cytoprotection against hepatic IRI and regulates liver apoptosis. Indeed, siRNA provides a powerful tool with which to study gene function in a wide range of liver diseases.
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