Genetic ablation of the transcription repressor Bach1 leads to myocardial protection against ischemia/reperfusion in mice

• Published in: Genes to cells : devoted to molecular & cellular mechanisms 2006-07, Vol.11 (7), p.791-803
• Main Authors: Yano, Yoko, Ozono, Ryoji, Oishi, Yoshihiko, Kambe, Masayuki, Yoshizumi, Masao, Ishida, Takafumi, Omura, Shinji, Oshima, Tetsuya, Igarashi, Kazuhiko
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - physiology; Basic-Leucine Zipper Transcription Factors - deficiency; Basic-Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors - metabolism; Heart Ventricles - metabolism; Heme Oxygenase-1 - metabolism; Immunohistochemistry; Male; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Myocardial Infarction - genetics; Myocardial Infarction - metabolism; Myocardial Infarction - prevention & control; Myocardial Ischemia - genetics; Myocardial Ischemia - metabolism; Reperfusion Injury - genetics; Reperfusion Injury - metabolism; Reperfusion Injury - prevention & control
• ISSN: 1356-9597; 1365-2443
• DOI: 10.1111/j.1365-2443.2006.00979.x

Bach1 is a transcriptional repressor of heme oxygenase‐1 gene (Hmox‐1) and β‐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.