title: Myocardial protection against pressure overload in mice lacking Bach1, a transcriptional repressor of heme oxygenase-1.
abstract: Bach1 is a stress-responsive transcriptional factor that is thought to control the expression levels of cytoprotective factors, including heme-oxygenase (HO)-1. In the present study, we investigated the roles of Bach1 in the development of left ventricular (LV) hypertrophy and remodeling induced by transverse aortic constriction (TAC) in vivo using Bach1 gene-deficient (Bach1(-/-)) mice. TAC for 3 weeks in wild-type control (Bach1(+/+)) mice produced LV hypertrophy and remodeling manifested by increased heart weight, histological findings showing increased myocyte cross-sectional area (CSA) and interstitial fibrosis (picro Sirius red staining), reexpressions of ANP, BNP, and betaMHC genes, and echocardiographic findings showing wall thickening, LV dilatation, and reduced LV contraction. Deletion of Bach1 caused significant reductions in heart weight (by 16%), CSA (by 36%), tissue collagen content (by 38%), and gene expression levels of ANP (by 75%), BNP (by 45%), and betaMHC (by 74%). Echocardiography revealed reduced LV dimension and ameliorated LV contractile function. Deletion of Bach1 in the LV caused marked upregulation of HO-1 protein accompanied by elevated HO activity in both basal or TAC-stimulated conditions. Treatment of Bach1(-/-) mice with tin-protoporphyrin, an inhibitor of HO, abolished the antihypertrophic and antiremodeling effects of Bach1 gene ablation. These results suggest that deletion of Bach1 caused upregulation of cytoprotective HO-1, thereby inhibiting TAC-induced LV hypertrophy and remodeling, at least in part, through activation of HO. Bach1 repressively controls myocardial HO-1 expression both in basal and stressed conditions, inhibition of Bach1 may be a novel therapeutic strategy to protect the myocardium from pressure overload.
authors.affiliation: Department of Cardiovascular Physiology and Medicine, Hiroshima University Graduate School of Biomedical Sciences, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Mito
authors.forename: Ryoji
authors.initials: R
authors.lastname: Ozono
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Oshima
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yano
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Watari
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Andrei
authors.initials: A
authors.lastname: Brydun
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Igarashi
authors.forename: Masao
authors.initials: M
authors.lastname: Yoshizumi
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D001794:Blood Pressure; D001835:Body Weight; D004452:Echocardiography; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006339:Heart Rate; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D006973:Hypertension / Q000150:complications* / Q000473:pathology / Q000503:physiopathology*; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000209:etiology* / Q000503:physiopathology*; D007501:Iron / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology; D018384:Oxidative Stress / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology
chemical_list: C486316:Bach1 protein, mouse; D050976:Basic-Leucine Zipper Transcription Factors; D007501:Iron; D051547:Heme Oxygenase-1