Suppression of indomethacin-induced apoptosis in the small intestine due to Bach1 deficiency

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.

Bach1Deficiency and Accompanying Overexpression of Heme Oxygenase-1 Do Not Influence Aging or Tumorigenesis in Mice

“…We need to examine whether Bach1 deficiency modulates ROS metabolism when mice are challenged with oxidative stress. The results suggest that a targeting of Bach1 in medical treatment is acceptable for acute and chronic injuries without any long-term side effect as shown in several papers [1, 26, 28, 29, 31, 45]. …”

“…Despite the growing number of evidences that inhibition of Bach1 may be beneficial in certain clinical situations [1, 26, 28, 29, 31, 45], the long-term, organismal response to Bach1 ablation has not yet been examined. Considering its distinct effects on ROS homeostasis and cell proliferation, Bach1 deficiency may affect the aging and/or life span in mice under normal conditions; ROS levels would decrease via the derepression of HO-1, and/or the p53-dependent cellular senescence would be increased by the enhanced activity of p53.…”

Wearing Red for Signaling: The Heme-Bach Axis in Heme Metabolism, Oxidative Stress Response and Iron Immunology

“…A reduced level of apoptotic cells and a higher expression of HO-1 are observed in the intestines of these mice compared to wild-type mice (Harusato et al 2009(Harusato et al , 2011. In addition, the development of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis is suppressed in Bach1-deficient mice (Harusato et al 2013), and the HO-1 expression is highly induced in the mucosa of these mice.…”

“…system/organ effects of Bach1-deficiency references blood vessel reduction of cuff injyury with reduced smooth muscle proliferation (Omura et al, 2005) reduction in atherosclerosis in Apo E kockout mice ) heart reduction in I/R injury (Yano et al, 2006) reduced hypertrophy after pressure overload lung reduced damages after high oxygen exposure (Tanimoto et al, 2009) intestine reduced injury in small intestine after indomethacin administration (Harusato et al, 2011;Harusato et al, 2009) reduction in trinitrobenzene sulfonic acid (TNBS)-induced colitis (Harusato et al, 2013) liver reduction in steatohepatitis induced by methionine-choline deficient diet reduced damages induced by D-galactosamine and lipopolysaccharide (Iida et al, 2009) pancreas reduction of apoptosis of beta cells and less increase of blood glucose upon alloxan treatment (Kondo et al, 2013) intervertebral disc reduced damages in annulus puncture model (Ochiai et al, 2008) spinal cord reduced damages after mechanical injury and better locomoter activity (Kanno et al, 2009;Yamada et al, 2008) type mice and reduced areas of infarction after I/R (Yano et al 2006). Cardiac hypertrophy is a compensatory mechanism of the heart that functions to maintain cardiac output in the presence of sustained increases in the hemodynamic load, although it can lead to the development of cardiac failure.…”

Hemopexin is upregulated in rat intestinal mucosa injured by indomethacin

“…Recent evidence indicates that HO-1 plays a potent protective role against NSAID-induced small intestinal injuries. 21 MASCOT score describes the significance of the search results from the search engine MASCOT and a significance threshold of 60 is typical. The sequence coverage was defined as the ratio of the number of the identified amino acids to the total number of amino acids of the protein (%).…”