Effects of genetic ablation of <i>bach1</i> upon smooth muscle cell proliferation and atherosclerosis after cuff injury

Omura, Shinji; Sano, Hiroshi; Toyofuku, Mamoru; Ozono, Ryoji; Kohno, Nobuoki; Igarashi, Kazuhiko

doi:10.1111/j.1365-2443.2005.00832.x

Cited by 53 publications

(59 citation statements)

References 42 publications

(85 reference statements)

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“…(28,29) Bach1-deficient mice, in which HO-1 expression is increased in myocardial and smooth muscle cells, are resistant to ischemic and pro-atherosclerotic stresses. (30,31) Despite these previous findings, there is little information about HO-1 expression in leukemic cells from AML patients. In this study, we investigated the expression of HO-1 and its regulatory mechanisms by Nrf2 and Bach1 in human AML cells as well as mature monocytes and leukemic cell lines.…”

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confidence: 80%

Expression of heme oxygenase‐1 in human leukemic cells and its regulation by transcriptional repressor Bach1

et al. 2010

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Heme oxygenase (HO)-1 has anti-oxidative, anti-inflammatory, and anti-apoptotic activities. However, little is known about the regulation of HO-1 in human primary acute myeloid leukemia (AML) cells. Here we investigated the expression of HO-1 in primary and established AML cells as well as other types of leukemic cells and normal monocytes, and its regulatory mechanism by the transcriptional repressor, BTB and CNC homology 1 (Bach1), and the activator, nuclear factor erythroid-derived 2 related factor 2 (Nrf2). Leukemic cell lines such as U937 expressed little HO-1, whereas most freshly isolated AML cells and monocytes expressed substantial amounts of HO-1, along with Bach1 and Nrf2. When U937 cells were treated with phorbol myristate acetate (PHA) or c-interferon, they significantly expressed both HO-1 and Bach1, like primary AML cells. Treatment with lipopolysaccharide (LPS) enhanced HO-1 expression in U937 cells but suppressed it in primary monocytes and PMA-treated U937 cells. In HO-1-expressing cells, Bach1 was localized in the cytoplasm, but Nrf2 was localized in the nuclei. Chromatin immunoprecipitation assay of these cells revealed the preferential binding of Nrf2 over Bach1 to Maf-recognition elements, the enhancer regions of the HO-1 gene. The downregulation of the HO-1 gene with siRNA increased a cytotoxic effect of an anticancer drug on primary AML cells, whereas the downregulation of Bach1 increased HO-1 expression, leading to enhanced survival. These and other results show that Bach1 plays a critical role in regulating HO-1 gene expression in AML cells and its expression suppresses their survival by downregulating HO-1 expression. Thus, functional upregulation of Bach1 is a potential strategy for antileukemic therapy. (Cancer Sci 2010; 101: 1409-1416 H eme oxygenase (HO)-1 is an inducible form of HO, which degrades heme into carbon monoxide, Fe 2+ , and biliverdin. HO-1 possesses cytoprotective properties such as antioxidative, anti-inflammatory, and anti-apoptotic functions, and these properties are beneficial to cells, tissues, organs, and organisms.(1,2) Accumulating evidence shows that induction of HO-1 is a promising strategy for the treatment of various ischemic and inflammatory diseases.(1-3) In addition, HO-1 is a potential target for cancer therapy because this enzyme gives survival and growth advantages to malignant cells by means of its anti-apoptotic activity.(4-8) Aberrant expression of HO-1 in human cancers, including hematological malignancies, is implicated in oncogenesis and chemoresistance. In primary CML cells and the CML-derived K562 cell line, constitutively expressed HO-1 has been identified as a BCR ⁄ ABL oncoprotein-dependent survival factor.(9) Other studies have shown that modulation of HO-1 expression affects cellular growth or survival of myeloid leukemia cells.(10-12) Therefore, understanding the regulatory system for the HO-1 expression in myeloid lineage cells seems to be critically important.HO-1 is induced in response to oxidative stress, and its expression is regul...

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confidence: 80%

Expression of heme oxygenase‐1 in human leukemic cells and its regulation by transcriptional repressor Bach1

et al. 2010

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“…Upon association with heme, Bach1 loses its DNA-binding activity and is exported out of nuclei, which results in unlimited upregulation of HO-1 transcription depending on the extent of stimuli (29). This inactivation of Bach1 is a common process in the signaling pathways of HO-1 upregulation, including that derived from oxidized LDL (47). Thus, it is reasonable to study the role of HO-1 in the mechanisms of atherosclerosis based on the response of HO-1 mRNA to hemin.…”

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confidence: 99%

Reduced Expression of Heme Oxygenase-1 in Patients with Coronary Atherosclerosis

et al. 2007

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“…Higher expression of HO-1 in Bach1 Ϫ/Ϫ mice has been shown to lead to decreased tissue damage in diseases such as arteriosclerosis (34), ischemic reperfusion of the heart (35), and in spinal cord injury (36). In these models, heme may be released from damaged cells and used as a substrate for HO-1.…”

Section: Discussionmentioning

confidence: 99%

Bach1-dependent and -independent Regulation of Heme Oxygenase-1 in Keratinocytes

Okada

Muto

Ogawa

et al. 2010

Journal of Biological Chemistry

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Bach1 is a member of the basic leucine zipper transcription factor family, and the Bach1/small Maf heterodimer specifically represses transcriptional activity directed by the Maf recognition element (MARE). Because Bach1 is a repressor of the oxidative stress response, we examined the function(s) of Bach1 in keratinocytes subjected to oxidative stress. Oxidative stress induced by H 2 O 2 led to an increase in MARE activity and expression of heme oxygenase-1 (HO-1), an inducible antioxidant defense enzyme. Bach1 depletion by small interfering RNAs or by deletion of Bach1 enhanced HO-1 expression in the absence of H 2 O 2 , indicating that Bach1 is a critical repressor of HO-1 in keratinocytes. Although Bach1-deficient or -reduced keratinocytes expressed higher levels of HO-1 than control cells in response to H 2 O 2 , Bach1 down-regulation did not attenuate the production of reactive oxygen species by H 2 O 2 . In contrast, Bach1 overexpression abolished HO-1 induction by H 2 O 2 , which led to increased reactive oxygen species accumulation. HO-1 was induced during keratinocyte differentiation, but MARE activity did not change during differentiation. Furthermore, Bach1 overexpression did not inhibit differentiation-associated induction of HO-1 expression, suggesting that HO-1 induction in differentiation is independent of Bach1. Thus, in response to oxidative stress, Bach1 regulates the oxidation state through the negative control of HO-1 expression prior to terminal keratinocyte differentiation. However, Bach1-mediated repression is negated during keratinocyte differentiation.Redox regulation is critical to cell survival, because cells cannot avoid endogenous reactive oxygen species (ROS) 2 that are generated as by-products of respiration (1). The skin is constantly exposed to harmful ROS that are generated by prooxidant agents in the environment, as well as by endogenous cellular oxidants. Thus, keratinocytes strongly and constitutively express ROS-detoxifying enzymes, including superoxide dismutase, catalase, glutathione peroxidase, and reductase, and contain substantial levels of the antioxidants tocopherol and ubiquinol (2, 3). Additionally, these cells possess an inducible defense system that includes heme oxygenase-1 (HO-1) (3-5). An imbalance between ROS and antioxidants can lead to the generation of high oxidant levels, which play a pivotal role in skin aging and disease (6).The transcription factor Bach1 is a repressor of the oxidative stress response in higher eukaryotes (7,8) and, together with its paralogue Bach2, constitutes a subfamily of the basic leucine zipper family of proteins. Bach1 forms heterodimers with the basic leucine zipper subfamily of small Maf proteins (i.e. MafF, MafG, and MafK), which bind the Maf recognition element (MARE) in the promoter regions of genes such as HO-1, NADP(H) quinone (oxido)reductase, and ␤-globin (7, 9, 10), and thereby repress transcription in the absence of oxidative stress. In the presence of oxidative stress, Bach1 is inactivated (11, 12), which allows tran...

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Effects of genetic ablation of bach1 upon smooth muscle cell proliferation and atherosclerosis after cuff injury

Cited by 53 publications

References 42 publications

Expression of heme oxygenase‐1 in human leukemic cells and its regulation by transcriptional repressor Bach1

Expression of heme oxygenase‐1 in human leukemic cells and its regulation by transcriptional repressor Bach1

Reduced Expression of Heme Oxygenase-1 in Patients with Coronary Atherosclerosis

Bach1-dependent and -independent Regulation of Heme Oxygenase-1 in Keratinocytes

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