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.
Yoshida
T
T
Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT 06030-1110, USA.
Maulik
N
N
Ho
Y S
YS
Alam
J
J
Das
D K
DK
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