Basal rather than induced heme oxygenase-1 levels are crucial in the antioxidant cytoprotection.
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-alpha, IL-6, and IFN-gamma) 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.
Tsuchihashi
Sei-ichiro
S
Division of Liver and Pancreas Transplantation, Department of Surgery, Dumont-University of California Los Angeles Transplant Center, Los Angeles, CA 90095, USA.
Livhits
Masha
M
Zhai
Yuan
Y
Busuttil
Ronald W
RW
Araujo
Jesus A
JA
Kupiec-Weglinski
Jerzy W
JW
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis; D019610:Cytoprotection / Q000502:physiology*; D004195:Disease Models, Animal; D051547:Heme Oxygenase-1 / Q000187:drug effects / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects; D011524:Protoporphyrins / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D015427:Reperfusion Injury / Q000201:enzymology* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000975:Antioxidants; D016207:Cytokines; D011524:Protoporphyrins; D012333:RNA, Messenger; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1