Hmox-1 constitutes an adaptive response to effect antioxidant cardioprotection - A study with transgenic mice heterozygous for targeted disruption ofthe heme oxygenase-1 gene

Background--Heme oxygenase-1 (Hmox-1) has been implicated in protection of cells against ischemia/reperfusion injury. Methods and Results-To examine the physiological role of Hmox-1, a line of heterozygous Hmox-1-knockout mice was developed by targeted disruption of t he mouse Hmox-1 gene. Transgene integration was confirmed and characterized at the protein level A 40% reduction of Hmox-1 protein occurred in the hea rts of H-mox-1(+/-) mice compared with those of wild-type mice. Isolated mo use hearts from H-mox-1(+/-) mice and wild-type controls perfused via the L angendorff mode were subjected to 30 minutes of ischemia followed by 120 mi nutes of reperfusion. The H-mox-1(+/-) hearts displayed reduced ventricular recovery, increased creatine kinase release, and increased infarct size co mpared 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 subjecte d to increased amounts of oxidative stress. Treatment with 2 different anti oxidants, 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 ada pt the hearts of the H-mox-1(+/-) mice compared with wild-type hearts. Conclusions These results demonstrate that Hmox-1 plays a crucial role in i schemia/reperfusion injury not only by functioning as an intracellular anti oxidant but also by inducing its own expression under stressful. conditions such as preconditioning.