H(mox-1) constitutes an adaptive response to effect antioxidant cardioprotection: A study with transgenic mice heterozygous for targeted disruption of the Heme oxygenase-1 gene.
BACKGROUND
Heme oxygenase-1 (H(mox-1)) has been implicated in protection of cells against ischemia/reperfusion injury.


RESULTS
To examine the physiological role of H(mox-1), a line of heterozygous H(mox-1)-knockout mice was developed by targeted disruption of the mouse H(mox-1) gene. Transgene integration was confirmed and characterized at the protein level. A 40% reduction of H(mox-1) protein occurred in the hearts of H(mox-1)(+/)(-) mice compared with those of wild-type mice. Isolated mouse hearts from H(mox-1)(+/)(-) mice and wild-type controls perfused via the Langendorff mode were subjected to 30 minutes of ischemia followed by 120 minutes of reperfusion. The H(mox-1)(+/)(-) hearts displayed reduced ventricular recovery, increased creatine kinase release, and increased infarct size compared with those of wild-type controls, indicating that these H(mox-1)(+/)(-) hearts were more susceptible to ischemia/reperfusion injury than wild-type controls. These results also suggest that H(mox-1)(+/)(-) hearts are subjected to increased amounts of oxidative stress. Treatment with 2 different antioxidants, Trolox or N:-acetylcysteine, only partially rescued the H(mox-1)(+/)(-) hearts from ischemia/reperfusion injury. Preconditioning, which renders the heart tolerant to subsequent lethal ischemia/reperfusion, failed to adapt the hearts of the H(mox-1)(+/)(-) mice compared with wild-type hearts.


CONCLUSIONS
These results demonstrate that H(mox-1) plays a crucial role in ischemia/reperfusion injury not only by functioning as an intracellular antioxidant but also by inducing its own expression under stressful conditions such as preconditioning.
Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT 06030-1110, USA.
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T
Yoshida
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Maulik
Y S
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Ho
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Alam
D K
DK
Das
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002839:Chromans / Q000494:pharmacology; D003402:Creatine Kinase / Q000378:metabolism; D004195:Disease Models, Animal; D018390:Gene Targeting; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects / Q000235:genetics; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006579:Heterozygote; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial; D008315:Malondialdehyde / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics; D009203:Myocardial Infarction / Q000178:diet therapy / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000235:genetics; D009206:Myocardium / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
D000975:Antioxidants; D002839:Chromans; D008565:Membrane Proteins; D008315:Malondialdehyde; C038983:1,3-dimethylthiourea; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D003402:Creatine Kinase; D013890:Thiourea; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; D000111:Acetylcysteine