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* Division of Liver and Pancreas Transplantation, Department of Surgery, Dumont-University of California Los Angeles Transplant Center, Los Angeles, CA 90095;
Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, CA 90095; and
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, CA 90095
Heme oxygenase-1 (HO-1) overexpression protects against tissue injury in many inflammatory processes, including ischemia/reperfusion injury (IRI). This study evaluated whether genetically decreased HO-1 levels affected susceptibility to liver IRI. Partial warm ischemia was produced in hepatic lobes for 90 min followed by 6 h of reperfusion in heterozygous HO-1 knockout (HO-1+/–) and HO-1+/+ wild-type (WT) mice. HO-1+/– mice demonstrated reduced HO-1 mRNA/protein levels at baseline and postreperfusion. This corresponded with increased hepatocellular damage in HO-1+/– mice, compared with WT. HO-1+/– mice revealed enhanced neutrophil infiltration and proinflammatory cytokine (TNF-
, IL-6, and IFN-
) induction, as well as an increase of intrahepatic apoptotic TUNEL+ cells with enhanced expression of proapoptotic genes (Bax/cleaved caspase-3). We used cobalt protoporphyrin (CoPP) treatment to evaluate the effect of increased baseline HO-1 levels in both WT and HO-1+/– mice. CoPP treatment increased HO-1 expression in both animal groups, which correlated with a lower degree of hepatic damage. However, HO-1 mRNA/protein levels were still lower in HO-1+/– mice, which failed to achieve the degree of antioxidant hepatoprotection seen in CoPP-treated WT. Although the baseline and postreperfusion HO-1 levels correlated with the degree of protection, the HO-1 fold induction correlated instead with the degree of damage. Thus, basal HO-1 levels are more critical than the ability to up-regulate HO-1 in response to the IRI and may also predict the success of pharmacologically induced cytoprotection. This model provides an opportunity to further our understanding of HO-1 in stress defense mechanisms and design new regimens to prevent IRI.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants RO1 DK062357, AI23847, AI42223 (to J.W.K.-W.), PO1 HL30568 (to J.A.A.), the Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program (to J.A.A.), the Roche Transplant Foundation (to Y.Z.), the Sarnoff Endowment (M.L.), and the Dumont Research Foundation.
2 S.-i.T. and M.L. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Jesus A. Araujo, Division of Cardiology, UCLA, 10833 Le Conte Avenue, CHS BH-307, Los Angeles, CA 90095-7054. E-mail address: Jaraujo{at}mednet.ucla.edu
4 J.A.A. and J.W.K.-W. contributed equally to this work.
5 Abbreviations used in this paper: IRI, ischemia/reperfusion injury; HO, heme oxygenase; WT, wild type; KO, knockout; CoPP, cobalt protoporphyrin; sGOT, serum glutaminic oxaloacetic transaminase; sGPT, serum glutaminic pyruvic transaminase; MPO, myeloperoxidase; PMN, polymorphonuclear neutrophil.
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  N. G. Abraham and A. Kappas Pharmacological and Clinical Aspects of Heme Oxygenase Pharmacol. Rev., March 1, 2008; 60(1): 79 - 127. [Abstract] [Full Text] [PDF]
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 M. Cudmore, S. Ahmad, B. Al-Ani, T. Fujisawa, H. Coxall, K. Chudasama, L. R. Devey, S. J. Wigmore, A. Abbas, P. W. Hewett, et al. Negative Regulation of Soluble Flt-1 and Soluble Endoglin Release by Heme Oxygenase-1 Circulation, April 3, 2007; 115(13): 1789 - 1797. [Abstract] [Full Text] [PDF]
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