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Genetic ablation of the transcription repressor Bach1 leads to myocardial protection against ischemia/reperfusion in mice
Author(s) -
Yano Yoko,
Ozono Ryoji,
Oishi Yoshihiko,
Kambe Masayuki,
Yoshizumi Masao,
Ishida Takafumi,
Omura Shinji,
Oshima Tetsuya,
Igarashi Kazuhiko
Publication year - 2006
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2006.00979.x
Subject(s) - biliverdin , biology , heme oxygenase , repressor , cardioprotection , heme , gene expression , gene , ischemia , medicine , biochemistry , enzyme
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.