(Circulation. 2001;103:1695.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Hmox-1 Constitutes an Adaptive Response to Effect Antioxidant Cardioprotection
A Study With Transgenic Mice Heterozygous for Targeted Disruption of the Heme Oxygenase-1 Gene
From the Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington (T.Y., N.M., D.K.D.); the Institute of Chemical Toxicology, Wayne State University, Detroit, Mich (Y.-S.H.); and the Department of Molecular Genetics, Louisiana University Medical Center, New Orleans (J.A.).
Correspondence to Dipak K. Das, PhD, University of Connecticut, School of Medicine, Farmington, CT 06030-1110. E-mail ddas{at}neuron.uchc.edu
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 the mouse Hmox-1 gene. Transgene integration was confirmed and characterized at the protein level. A 40% reduction of Hmox-1 protein occurred in the hearts of Hmox-1+/- mice compared with those of wild-type mice. Isolated mouse hearts from Hmox-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 Hmox-1+/- hearts displayed reduced ventricular recovery, increased creatine kinase release, and increased infarct size compared with those of wild-type controls, indicating that these Hmox-1+/- hearts were more susceptible to ischemia/reperfusion injury than wild-type controls. These results also suggest that Hmox-1+/- hearts are subjected to increased amounts of oxidative stress. Treatment with 2 different antioxidants, Trolox or N-acetylcysteine, only partially rescued the Hmox-1+/- hearts from ischemia/reperfusion injury. Preconditioning, which renders the heart tolerant to subsequent lethal ischemia/reperfusion, failed to adapt the hearts of the Hmox-1+/- mice compared with wild-type hearts.
Conclusions—These results demonstrate that Hmox-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.
Key Words: heme oxygenase • genes • oxygen • stress • ischemia
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