Myocardial protection against pressure overload in mice lacking bachl, a transcriptional repressor of heme oxygenase-1

Shinji Mito, Ryoji Ozono, Tetsuya Oshima, Yoko Yano, Yuichiro Watari, Yoshiyuki Yamamoto, Andrei Brydun, Kazuhiko Igarashi, Masao Yoshizumi

研究成果: Article査読

63 被引用数 (Scopus)

抄録

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 βMHC 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 βMHC (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.

本文言語English
ページ(範囲)1570-1577
ページ数8
ジャーナルHypertension
51
6
DOI
出版ステータスPublished - 2008 6月 1

ASJC Scopus subject areas

  • 内科学

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