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.

Abstract

BACKGROUND:

Heme oxygenase-1 (H(mox-1)) has been implicated in protection of cells against ischemia/reperfusion injury.

METHODS AND 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.

• Authors: T Yoshida, N Maulik, Y S Ho, J Alam, D K Das
• Journal: Circulation (Circulation) Vol. 103 Issue 12 Pg. 1695-701 (Mar 27 2001) ISSN: 1524-4539 [Electronic] United States
• PMID: 11273999 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antioxidants
• Chromans
• Membrane Proteins
• Malondialdehyde
• 1,3-dimethylthiourea
• Heme Oxygenase (Decyclizing)
• Heme Oxygenase-1
• Hmox1 protein, mouse
• Creatine Kinase
• Thiourea
• 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
• Acetylcysteine

Topics

• Acetylcysteine (pharmacology)
• Animals
• Antioxidants (pharmacology)
• Chromans (pharmacology)
• Creatine Kinase (metabolism)
• Disease Models, Animal
• Gene Targeting
• Heart (drug effects)
• Heart Rate (drug effects, genetics)
• Heme Oxygenase (Decyclizing) (genetics, metabolism)
• Heme Oxygenase-1
• Heterozygote
• In Vitro Techniques
• Ischemic Preconditioning, Myocardial
• Malondialdehyde (metabolism)
• Membrane Proteins
• Mice
• Mice, Transgenic
• Myocardial Contraction (drug effects, genetics)
• Myocardial Infarction (diet therapy, genetics, pathology, prevention & control)
• Myocardial Ischemia (enzymology, genetics)
• Myocardium (metabolism)
• Reperfusion Injury (enzymology, genetics, pathology, prevention & control)
• Thiourea (analogs & derivatives, pharmacology)