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¹ Departments of Clinical Laboratory Medicine,
² Biomedical Chemistry,
³ Cardiovascular Physiology and Medicine, and ⁴ Medicine and Molecular Science, Hiroshima University Graduate School of Biomedical Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan

Bach1 is a transcriptional repressor of heme oxygenase-1 gene (Hmox-1) and ß-globin gene. Heme oxygenase (HO)-1 is an inducible cytoprotective enzyme that degrades pro-oxidant heme to carbon monoxide (CO) and biliverdin/bilirubin, which are thought to mediate anti-inflammatory and anti-oxidant actions of HO-1. In the present study, we investigated the role of Bach1 in tissue protection against myocardial ischemia/reperfusion (I/R) injury in vivo using mice lacking the Bach1 gene (Bach1^–/–) and wild-type (Bach1^+/+) mice. In Bach1^–/– mice, myocardial expression of HO-1 protein was constitutively up-regulated by 3.4-fold compared to that in Bach1^+/+ mice. While myocardial I/R induced HO-1 protein in ischemic myocytes in both strains of mice, the extent of induction was significantly greater in Bach1^–/– mice than in Bach1^+/+ mice. Myocardial infarction was markedly reduced in size by 48.4% in Bach1^–/– mice. Pretreatment of Bach1^–/– mice with zinc-protoporphyrin, an inhibitor of HO activity, abolished the infarction-reducing effect of Bach1 disruption, indicating that reduction in the infarct size was mediated, at least in part, by HO-1 activity. Thus, Bach1 plays a pivotal role in setting the levels of both constitutive and inducible expression of HO-1 in the myocardium. Bach1 inactivation during I/R appears to be a key mechanism controlling the activation level of cytoprotective program involving HO-1.

^aPresent address: Department of Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba-ku, Sendai 980-8575, Japan

^* Correspondence: E-mail: ozono{at}hiroshima-u.ac.jp

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