Heme oxygenase-1 gene transfer inhibits inducible nitric oxide synthase expression and protects genetically fat Zucker rat livers from ischemia-reperfusion injury1

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Abstract
Background. Ischemia/reperfusion (I/R) injury is a critical factor in the dysfunction of steatotic orthotopic liver transplants. Heme oxygenase-1 (HO-1), a cytoprotective protein, may be important in ameliorating hepatic I/R injury. Methods. We used adenovirus (Ad)-based HO-1 gene transfer to analyze the effects of HO-1 overexpression in a well-established fatty Zucker rat model of I/R followed by orthotopic liver transplantation. Results. Ad-HO-1 gene therapy increased recipient survival (80% vs. 40–50% in controls) and significantly diminished hepatocyte injury, as compared with untreated and Ad-β-galactosidase (Ad-β-Gal)–treated livers. Orthotopic liver transplants in the Ad-HO-1 group exhibited less macrophage infiltration in the portal areas, as compared with controls. Unlike untreated and Ad-β-Gal–treated orthotopic liver transplant controls, which showed elevated levels of inducible nitric oxide synthase by infiltrating macrophages, inducible nitric oxide synthase expression in the Ad-HO-1 group was almost absent. In contrast, endothelial nitric oxide synthase was comparable in Ad-HO-1– and Ad-β-Gal–transduced fatty orthotopic liver transplants. Intragraft expression of antiapoptotic Bcl-2 and Bag-1 was increased in Ad-HO-1–treated orthotopic liver transplants, as compared with Ad-β-Gal controls. Moreover, increased HO enzymatic activity was accompanied by inhibition of caspase-3 protein expression. Conclusions. HO-1 gene transfer significantly prolongs survival of steatotic orthotopic liver transplants, depresses macrophage infiltration, suppresses local expression of inducible nitric oxide synthase, and modulates pro- and antiapoptotic pathways.