H mox-1 Constitutes an Adaptive Response to Effect Antioxidant Cardioprotection

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.