Basal Rather Than Induced Heme Oxygenase-1 Levels Are Crucial in the Antioxidant Cytoprotection

Abstract

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-α, IL-6, and IFN-γ) 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.

Heme Oxygenase-1 Expression in Macrophages Plays a Beneficial Role in Atherosclerosis

“…13, 23 The present study demonstrates that HO-1 expression in macrophages constitutes an important component of We and others have previously demonstrated that HO-1 ϩ/Ϫ mice can serve as an in vivo model of decreased HO-1 expression. Livers from HO-1 ϩ/Ϫ mice exhibit Ϸ32% baseline mRNA and Ϸ41% protein of WT littermates, 24 similar to hearts from HO-1 ϩ/Ϫ mice, which also showed 41% protein compared with WT littermates. 25 Decreased HO-1 expression levels resulted in a proportional reduction in tissue HO enzyme activity (supplemental Figure I) and significant aggravation of outcomes in models of liver 24 and cardiac 25 ischemia reperfusion, where the reintroduction of ROS after a period of ischemia plays a predominant pathogenic role.…”

“…Differences in HO-1 expression levels did not result in any compensatory changes in HO-2 mRNA ( Figure 1B). Decreased HO-1 expression in HO-1 ϩ/Ϫ macrophages paralleled decreased tissue expression of HO-1 in these systemic KO mice in livers, 24 spleens, heart, kidney, and aorta (data not shown). Decreased and absence of HO-1 expression resulted in a concomitant reduction in tissue HO enzyme activity, as demonstrated in liver microsomes from HO-1 ϩ/Ϫ and HO-1 Ϫ/Ϫ mice (supplemental Figure I).…”

Oligosaccharides from Agar Inhibit Pro-Inflammatory Mediator Release by Inducing Heme Oxygenase 1

“…Indeed, the beneficial effects of HO-1 on various inflammatory diseases (e.g., RA, colitis and ischemia/reperfusion injury) have been reported. [19][20][21][22][23] Choi et al 15) have reported that CO suppressed the production of such pro-inflammatory cytokines as TNF-, IL-1, MIP-1 and MIP-2 in activated macrophages. In fact, AB inhibited the generation of these cytokines in LPS-stimulated human monocytes.…”

Molecular Mediators of Liver Ischemia and Reperfusion Injury: A Brief Review

“…Ad-HO-1 overexpression also prevented CD95/FasL-mediated apoptosis, thereby improving liver function (69,70). Recently, a warm liver IRI model using wild-type and heterozygous HO-1-deficient (HO-1 +/-) mice demonstrated that basal HO-1 levels are more important than the upregulation of HO-1 in response to IR (71). Pretreatment with inhaled anesthetic isoflurane has also shown hepatoprotection in liver IRI, through increasing local HO-1 mRNA/protein expression and HO-1 enzyme activity (72).…”