Expression of BTB and CNC homologue 1 (Bach1), a transcriptional repressor of heme oxygenase-1 (HO- 1) and a cytoprotective enzyme, is induced by various injuries, including oxidative stress [11,12]. Bach1 can bind Maf proteins and then act as a repressor of HO-1 via the Maf-recognition element (MARE) of the HO-1 promoter. Bach1 binds heme with high affinity, thus preventing it from binding to MARE, and regulates the nuclear export of Bach1.Thus, the repres- sor function of Bach1 is inhibited by heme [13–15]. To investigate the function of Bach1, homozygous deficient mice resistant to various injuries involving Suppression of indomethacin-induced apoptosis in the small intestine due to Bach1 deficiency AKIHITO HARUSATO 1 , YUJI NAITO 1 , TOMOHISA TAKAGI 1 , KAZUHIKO UCHIYAMA 1 , KATSURA MIZUSHIMA 1 , YASUKO HIRAI 1 , SHINYA YAMADA 1 , TOSHIFUMI TUJI 1 , HIROYUKI YORIKI 1 , RYUSUKE HORIE 1 , KEN INOUE 1 , KOHEI FUKUMOTO 1 , OSAMU HANDA 1 , TAKESHI ISHIKAWA 1 , SATOSHI KOKURA 1 , YUKIKO MINAMIYAMA 1 , HIROSHI ICHIKAWA 2 , AKIHIKO MUTO 3 , KAZUHIKO IGARASHI 3 & TOSHIKAZU YOSHIKAWA 1 1 Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan, 2 Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Tatara Miyakodani 1-3, 610-0394, Kyotanabe-City, Japan, and 3 Department of Biochemistry, Tohoku University School of Medicine, Seiryo-machi 2-1, Aoba-ku, Sendai, 980-8575, Japan (Received date: 22 November 2010; Accepted date: 18 March 2011) Abstract BTB and CNC homologue 1 (Bach1) is a transcriptional repressor of heme oxygenase-1 (HO-1). This study hypothesized that Bach1 plays an important role in the indomethacin-induced apoptosis in the case of small-intestinal mucosal injury. Eight-week-old male C57BL/6 (wild-type) and homozygous Bach1-deficient C57BL/6 mice were included in this study. Mucosal injuries induced by subcutaneously administering indomethacin were evaluated macroscopically, histologically and biochemically. Indomethacin-induced injuries were improved in Bach1-deficient mice. Immunohistochemistry showed an increase in the number of HO-1-positive cells, which were mainly F4/80 positive macrophages, in Bach1-deficient mice. Indomethacin administration increased the expression of HO-1 mRNA and protein in the small intestine in Bach1-deficient mice. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) staining showed that the extent of apoptosis was suppressed in Bach1-deficent mice. In conclusion, deficiency of the Bach1 gene inhibited apoptosis and thus suppressed mucosal injury, indicating that Bach1 is a novel therapeutic target for indomethacin-induced intestinal injury. Keywords: Non-steroidal anti-inflammatory drugs, apoptosis, small intestine, heme oxygenase-1, Bach1 Introduction Development of endoscopic diagnostic techniques for small intestine diseases, such as video capsule endos- copy [1] and balloon enteroscopy [2], has led to the revelation that non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin can induce intesti- nal mucosal injuries [3,4]. Although the pathophysi- ology of NSAID-induced intestinal injuries has been elucidated [5–10], practical therapies for such injuries are unavailable. Therefore, it is important to investigate preventive and therapeutic strategies for NSAID-induced intestinal injuries. Correspondence: Yuji Naito, MD, PhD, Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan. Tel: +81-75-251-5508. Fax: +81- 75-251-0710. Email: ynaito@koto.kpu-m.ac.jp Free Radical Research, June 2011; 45(6): 717–727 ISSN 1071-5762 print/ISSN 1029-2470 online © 2011 Informa UK, Ltd. DOI: 10.3109/10715762.2011.574287 Free Radic Res Downloaded from informahealthcare.com by Dr. Yuji Naito on 02/26/12 For personal use only.