Genetic ablation of the transcription repressor Bach1 leads to myocardial protection against ischemia/reperfusion in mice.
Bach1 is a transcriptional repressor of heme oxygenase-1 gene (Hmox-1) and beta-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.
Yano
Yoko
Y
Department of Clinical Laboratory Medicine, Hiroshima University Graduate School of Biomedical Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Ozono
Ryoji
R
Oishi
Yoshihiko
Y
Kambe
Masayuki
M
Yoshizumi
Masao
M
Ishida
Takafumi
T
Omura
Shinji
S
Oshima
Tetsuya
T
Igarashi
Kazuhiko
K
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D050976:Basic-Leucine Zipper Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006352:Heart Ventricles / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control
C486316:Bach1 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D008565:Membrane Proteins; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse