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1 Departments of Clinical Laboratory Medicine,
2 Biomedical Chemistry,
3 Cardiovascular Physiology and Medicine, and 4 Medicine and Molecular Science, Hiroshima University Graduate School of Biomedical Sciences, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan
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Abstract |
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Introduction |
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The inducible enhancers of Hmox-1 carry multiple Maf-recognition elements (MAREs). Heterodimers of the small Maf proteins and NF-E2-related factor 2 (Nrf2) activate Hmox-1 through binding to MAREs (Itoh et al. 1997; Alam et al. 1999; Ishii et al. 2000; Kataoka et al. 2001). In contrast, heterodimers of small Maf and Bach1 or Bach2 repress MARE-dependent transcription (Oyake et al. 1996). The ability of Nrf2 to activate Hmox-1 expression is greatly reduced in the presence of Bach1 (Sun et al. 2002, 2004). These observations suggest that the activity of Bach1 to repress Hmox-1 is dominant over the activity of Hmox-1 activators such as Nrf2 under normal conditions and that inactivation of Bach1 is a key mechanism of Hmox-1 induction (Sun et al. 2002, 2004). It is known that Hmox-1 is strongly induced by its substrate heme as well as by oxidative stress. Heme binds to Bach1 to inhibit its DNA binding activity and to induce its nuclear export (Ogawa et al. 2001; Sun et al. 2002, 2004; Suzuki et al. 2004). Oxidative stressors such as cadmium also induce nuclear export of Bach1 (Suzuki et al. 2003). On the other hand, signals from reactive oxygen species or electrophilic insults are reported to inactivate the ubiquitin-proteasome degradation pathway of Nrf2 in the cytoplasm (Kobayashi & Yamamoto 2005), allowing this transcriptional factor to translocate to the nuclei and activate its target genes including Hmox-1. Taken together, both inactivation of Bach1 and activation of Nrf2 in response to heme and/or oxidative stress appear to be decisive for deployment of the cytoprotective program, including activation of Hmox-1. By the same token, Bach1 may set a threshold for cell survival under stressful conditions through inhibiting downstream target genes including Hmox-1. In the present study, we tested this hypothesis using a myocardial ischemic injury model in vivo. The data demonstrated a dramatic increase in cardioprotection against ischemic stress in mice lacking Bach1 (Bach1–/– mice), providing new insights into the transcriptional program of cytoprotection as well as the therapy of ischemic disease.
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Results |
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Wild-type (Bach1+/+) mice and Bach1–/– mice showed no significant differences in body and heart weights, cardiac histology and cardiac geometry and function evaluated by ultrasonography (Table 1). Likewise, they showed no difference in basal systolic and diastolic blood pressures or heart rate (Table 2). These observations suggest that the absence of Bach1 does not affect normal myocardial structure and function. We induced myocardial ischemia in Bach1+/+ and Bach1–/– mice by ligating the left anterior descending artery (LAD) for 60 min followed by reperfusion for 24 h (ischemia and reperfusion, I/R). Twenty-four hours after induction of the myocardial I/R injury, there was no significant difference in mortality between Bach1+/+ and Bach1–/– mice (9.8% in Bach1+/+ and 7.7% in Bach1–/– mice). I/R injury caused significant reduction in systolic and diastolic blood pressures in Bach1+/+ mice but not in Bach1–/– mice (Table 2), suggesting that the impact of ischemic myocardial damage on systemic hemodynamics was smaller in the mutant mice. Heart rates were significantly increased in both strains of mice.
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We compared the effects of I/R on HO-1 protein levels in the LVs of Bach1+/+ mice and Bach1–/– mice 24 h after I/R by Western blotting (Fig. 1). LVs were dissected into non-ischemic and ischemic regions. In Bach1+/+ mice, I/R had no effect on HO-1 level in the non-ischemic region, whereas it caused an increase in HO-1 level in the ischemic region (by two-fold vs. that in sham-operated mice) (Fig. 1B). When Bach1+/+ mice were pretreated with hemin, an established inducer of HO-1, I/R caused increases in HO-1 levels not only in the ischemic region (by three-fold) but also in the non-ischemic region (by 1.9-fold). In Bach1–/– mice, the basal HO-1 level (i.e. that in sham-operated Bach1–/– mice) was 3.4-fold higher than that in Bach1+/+ mice (P < 0.01). I/R caused further up-regulation of HO-1 in both the non-ischemic region (by 1.7-fold vs. the basal level) and ischemic region (by 2.9-fold). Importantly, the absolute HO-1 protein levels in the non-ischemic and ischemic regions of Bach1–/– mice were significantly (P < 0.05) higher than those of the other two mouse groups, indicating that Bach1 plays an important role in setting the level of both constitutive and inducible expression of HO-1. However, as shown in Fig. 1C, Bach1 expression level examined by real-time PCR in the heart of Bach1+/+ mice was not altered either by I/R or treatment of mice with hemin or zinc-protoporphyrin (ZnPP), an inhibitor of HO-1, suggesting that the transcriptional control of Bach1 abundance is not likely to be the major mechanism of HO-1 up-regulation. Increase in HO-1 level in the non-ischemic regions of hemin-treated Bach1+/+ mice and Bach1–/– mice was unexpected, but this finding may indicate that the inducibility of Hmox-1 was sensitized in these mice, leading to induction by non-ischemic stress such as hemodynamic overload resulting from partial myocardial loss.
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We carried out immunohistochemical analysis to identify cells expressing HO-1. HO-1 was only scarcely present in the myocardium of sham-operated Bach1+/+ mice, but it was up-regulated mainly in cardiomyocytes in the presumptive ischemic region following I/R (Fig. 3A). HO-1 staining was very weak in the vascular smooth muscle layer (
-smooth muscle actin-positive) and endothelium (CD31-positive) before and after I/R in Bach1+/+ mice (Fig. 3B). On the other hand, HO-1 was abundant throughout the myocardium in sham-operated Bach1–/– mice and it was further up-regulated following I/R (Fig. 3A). HO-1 was positive in the smooth muscle layer and endothelium of vasculature in Bach1–/– mice before and after I/R (Fig. 3B). Interestingly, HO-1 was clearly observed in microvessels in the infarcted area in both Bach1+/+ and Bach1–/– mice (Fig. 3C). These results suggest that the regulation of HO-1 expression is different in large vessels and microvessels. Bach1 may inhibit HO-1 expression in larger vessels but not in microvessels after I/R injury in Bach1+/+ mice. Upon I/R, inflammatory cells infiltrate into the damaged area. HO-1 was abundant in CD68 positive- monocytes/macrophages in both Bach1+/+ and Bach1–/– mice (Fig. 3C). Taken together, the absence of Bach1 caused marked up-regulation of HO-1 not only in cardiomyocytes but also in vascular smooth muscle cells.
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-smooth muscle actin, was thinner in Bach1–/– mice than in Bach1+/+ mice, which was confirmed by a quantitative morphometric analysis (1226 ± 19.3 vs. 1840 ± 22.5 µm2 in Bach1–/– vs. Bach1+/+ mice, respectively; P < 0.05). This difference is thought to reflect a reduced ability of Bach1-deficient vascular smooth muscle cells to proliferate, which was found in our previous in vitro experiments (Omura et al. 2005). Reduction of infarct size following I/R in Bach1–/– mice
Having established that the genetic ablation of Bach1 leads to higher levels of HO-1 expression, we next compared the tissue damage following I/R injury. The myocardial area at risk (AAR; i.e. perfusion area of the occluded coronary artery) in the I/R and sham-operated hearts was evaluated 24 h after surgery by Evans Blue staining, and the size of myocardial infarction was determined by triphenyl-tetrazolium chloride (TTC) staining (Fig. 4A), which delineates staining-resistant infarcted myocardium out of red-stained viable myocardium. As expected, there was no significant difference in the AAR among the groups of mice (Fig. 4B). The infarct sizes were compared after adjusting the respective AARs. As shown in Fig. 4A,C, the size of myocardial infarction in Bach1+/+ mice after I/R reached 46.9 ± 1.6% of the AAR. Pretreatment of Bach1+/+ mice with hemin, an inducer of HO-1, reduced infarct size to 35.3 ± 1.4% of the AAR (Fig. 4A,C). In Bach1–/– mice, the infarct size was markedly reduced to 24.3 ± 1.3% of the AAR (Fig. 4A,C). The infarct size in Bach1–/– mice was significantly smaller than that in Bach1+/+ mice and hemin-treated Bach1+/+ mice (Fig. 4C).
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Inhibitions of apoptosis in Bach1–/– mice
To determine whether apoptosis is involved in the mechanism of the cardioprotection, we examined cleavage of procaspase-3 to caspase-3 in myocardial tissues. Caspase-3 was activated following I/R in Bach1+/+ mice as judged by the appearance of cleaved form, whereas the cleaved form of caspase-3 was not detected in Bach1–/– mice (Fig. 5A). Consistent with this finding, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assays revealed fewer apoptotic cells in the LV of Bach1–/– mice than in LV of Bach1+/+ mice (Fig. 5B,C). Here, we focused on the ischemic regions of LVs in the sections (see Experimental procedures). Judging from the histology, most of the TUNEL-positive cells appeared to be cardiomyocytes. These results indicate that apoptosis of myocardial cells following I/R was inhibited in Bach1–/– mice. These results suggest that the absence of Bach1 caused overall suppression of apoptotic loss of myocardial cells after I/R, which may, at least in part, explain the cytoprotection against I/R in Bach1–/– mice.
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Discussion |
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While several studies have established Hmox-1 as a target gene of Bach1 (Sun et al. 2002, 2004), there may be additional downstream target genes. Because identity of other downstream genes and their functions are not known at present, it has been unclear how cells and tissues respond to various stresses in the absence of Bach1 in vivo. If some of the downstream genes are pro-apoptotic, for example, their expressions are expected to increase in the Bach1-deficient cells, resulting in increased apoptosis in response to stress. In the present study, we demonstrated that the genetic ablation of Bach1 caused a marked reduction in myocardial infarction after I/R (Fig. 4). Thus, the net effect of Bach1-ablation in the myocardial cells and tissues was to increase resistance against stresses derived from I/R injury. Because the infarction-reducing effect of Bach1-ablation was abolished by pretreating mice with ZnPP, it was mediated, at least in part, by the increased levels of HO-1 expression and HO activity in Bach1–/– mice. We have previously reported that Bach1-deficient mice showed reduced neointimal formation in the cuff injury model for arteriosclerosis, in which smooth muscle cells from Bach1-deficient mice expressed higher levels of HO-1 compared with wild-type mice (Omura et al. 2005). Thus, results of our previous and present studies suggest Bach1 as a detrimental factor in atherosclerosis and myocardial I/R injury. Although oxidative stress associated with such disease conditions is expected to inhibit Bach1, residual levels of Bach1 function may suffice to preclude full deployment of downstream target genes such as HO-1.
Interestingly, the cardioprotection in the absence of Bach1 was associated with inhibition of the p38 MAPK pathway, activation of the STAT3 pathway, and inhibition of apoptosis (Fig. 5). It has been suggested that activation of p38 MAPK is a pro-apoptotic signal in the heart under ischemic conditions as demonstrated in cultured cardiomyocytes subjected to ischemic stress (Mackay & Mochly Rosen 1999), in I/R model of isolated heart (Ma et al. 1999), and in in vivo I/R model of mice (Kaiser et al. 2004). Thus, attenuation of p38 MAPK may have contributed to the reduced levels of apoptosis in the Bach1-deficient mice. On the other hand, the activation of STAT3 pathway promotes cytoprotection and inhibits apoptosis in ischemic conditions (Negoro et al. 2000; Xuan et al. 2001; Stephanou 2004). Accordingly, conditional knockout mice harboring a cardiomyocyte-restricted deletion of STAT3 display a larger infarct size and increased apoptosis after I/R compared with the control mice (Jacoby et al. 2003; Hilfiker-Kleiner et al. 2004). Taking our observations together with these reports, we envisage that the cardioprotection in Bach1–/– mice was mediated, at least in part, by activation of STAT3. In contrast, because the genetic ablation of Bach1 did not significantly affect the phosphorylation levels of Akt during I/R injury, this survival pathway appears less affected by the presence or absence of Bach1.
The molecular mechanisms that led to reduced phosphorylation of p38 MAPK and increased activation of STAT3 in the Bach1–/– hearts are not clear at present. Administration of ZnPP in Bach1–/– mice reversed these effects of Bach1-ablation on STAT3 activation and p38 MAPK inactivation (Fig. 6D), suggesting that these changes were secondary to the increased activity of HO-1. Accordingly, phosphorylation of p38 MAPK was inhibited by CO-releasing molecules in endothelin-stimulated cardiomyocytes in culture (Tongers et al. 2004), suggesting that CO, one of the reaction products of HO-1 reaction, regulates p38 MAPK activation in the heart. Alternatively, biliverdin and/or its reduced product bilirubin may be responsible for the reduction in p38 MAPK activation because they are potent anti-oxidant (Stocker et al. 1987). Since the STAT3 is activated by the interleukin (IL)-6 family of cytokines including IL-6 (Kukielka et al. 1995), cardiotrophin-1 (Pennica et al. 1995; Sheng et al. 1997), and leukemia inhibitory factor (Kunisada et al. 1996) and by granulocyte-colony-stimulating factor (G-CSF) (Harada et al. 2005), the activation of STAT3 we observed in the Bach1–/– mice may reflect modulation of such cytokine network by HO-1. Much remains to be understood about this interesting coordination of p38 MAPK and STAT3 pathways via HO-1 in cardiomyocytes.
Recently, HO-1 gene delivery has been shown to result in amelioration of not only ischemic heart disease (Yet et al. 2001; Melo et al. 2002; Vulapalli et al. 2002) but also atherosclerosis (Juan et al. 2001; Tulis et al. 2001), renal I/R injury (Blydt-Hansen et al. 2003), hypoxia-induced lung injury (Otterbein et al. 1999) and liver I/R injury (Amersi et al. 1999). The results of this study suggest a novel way to maximize the cytoprotective role of HO-1 in disease settings. Importantly, the induced levels of HO-1 were found much higher in hearts of Bach1–/– mice. Furthermore, stress-regulated induction of HO-1 was somehow retained in the absence of Bach1. Thus, because inhibition of Bach1 is expected to result in higher levels of HO-1 expression, Bach1 may be an excellent therapeutic target against I/R injury. Further studies of Bach1 may lead to a detailed understanding of the gene expression programs of oxidative stress response.
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Experimental procedures |
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We used pairs of adult male Bach1–/– and Bach1+/+ littermates aged of 8–10 weeks in this study (Sun et al. 2002). Heterozygous mice were intercrossed to obtain homozygous Bach1-deficient mice as well as control wild-type mice. Congenic Bach1-deficient mice were obtained by repeatedly backcrossing with C57BL/6 J mice at least up to 12 generations. All experimental procedures were approved and carried out in accordance with the Guidelines of Hiroshima University Graduate School of Biomedical Sciences.
Surgical procedure
We induced myocardial ischemia by ligating the LAD as previously described (Oishi et al. 2003). The LAD was ligated at 1.0 mm distal from the tip of the left appendix for a period of 60 min, and this was followed by releasing the ligation and closing the chest. Hearts were excised at 2 and 24 h after surgery or sham-operation and subjected to the following analyses.
Assessment of cardiac geometry and function by ultrasonography
Cardiac geometry and function were evaluated using an echocardiographic system (Toshiba SSA 550A) equipped with a 14-MHz linear transducer as previously described (Oishi et al. 2003). LV end diastolic- and end systolic-dimensions (LVDd and LVDs) were measured at the distal level of the papillary muscle using short-axis M-mode images. Three beats were averaged for each measurement. Percent fractional shortening (%FS) was calculated as:
[(LVDd – LVDs)/LVDd] x 100.
Quantification of myocardial infarct after I/R
After excision, hearts were perfused with 1.0% TTC (Sigma-Aldrich) in phosphate buffer (pH 7.4) to stain viable myocardium. The LAD was then re-occluded, and each heart was perfused with 10% Evans Blue (Sigma-Aldrich) to delineate the AAR, i.e. perfusion area of the LAD. The hearts were frozen, and each LV was cut into five transverse slices. The images of the slices were digitally analyzed for infarct area, ischemic area and total LV area using NIH image software. The ratio of AAR/total LV area and the ratio of infarct area/AAR were calculated and expressed as percentages as previously described (Maekawa et al. 2002).
Administration of an inducer or inhibitor of HO-1
We injected hemin (30 mg/kg, Sigma-Aldrich) intraperitoneally 24 h prior to the coronary ligation in order to induce HO-1. For the purpose of blockade of HO activity, we injected ZnPP (10 mg/kg, Sigma-Aldrich) 24 h prior to the coronary ligation as previously described (Hangaishi et al. 2000). ZnPP was dissolved in phosphate buffer with 0.1 M NaOH and neutralized with 0.1 M HCl immediately before administration and pH was maintained at 7.4.
Western blot analysis
For detection of HO-1 protein, LVs were excised 24 h after I/R and homogenized in a buffer containing 50 mM Tris (pH 7.5), 150 mM NaCl, 1 mM PMSF, 0.25 M sucrose, 0.5% deoxycholate, 2 µg/mL leupeptin and 2 µg/mL aprotinin. Before homogenization, LVs were dissected into non-ischemic and ischemic myocardial regions. The perfusion area of the LAD, which was almost constant in mice (Fig. 4B), was considered to be the ischemic region. For analyses of phosphorylation signals and procaspase-3 cleavage, LVs were similarly dissected into non-ischemic and ischemic regions and homogenized in a buffer containing 25 mM Tris-HCl, 150 mM NaCl, 5 mM EDTA, 25 mM NaF, 25 mM Na-pyrophosphate, 1% Triton X-100, 0.1% SDS, 0.5% deoxycholate, 10% glycerol, 1 mM vanadate and 100 mM Benzamisin. Protein (100 µg) of each heart homogenate was incubated with anti-HO-1 polyclonal antisera (a gift from Dr S. Taketani), as previously described (Oishi et al. 2003). Antibodies for protein kinase Akt, phospho-Akt (Ser473), p38 MAPK, phospho-p38 (Thr180/Tyr182), STAT3 and phospho-STAT3 (Tyr705) were purchased from Cell Signaling Technology. Antibody for JNK was from Santa Cruz Biotechnology and that for phospho-JNK (pTPpY) was from Promega. Anti-caspase-3 was purchased from Sigma. This antibody also recognized procaspase-3. To investigate the amount of phosphorylation levels, the hearts were analyzed at 2 and 24 h after reperfusion. The blotted membrane was re-probed with actin (DAKO, clone 1A4) or -tubulin (Santa Cruz Biotechnology) as an internal standard.
Real-time PCR analysis for Bach1 expression
Total RNA was extracted from the cardiac tissues using Trizol, and cDNA was prepared as previously described (Sun et al. 2002). Real-time PCR was carried out using the LightCycler system (Roche), as previously described (Sun et al. 2002; Omura et al. 2005). Primers to amplify Bach1 cDNA were 5'-TGATGTGACTGTCCTGGTGG-3' and 5'-AAATCCTTTAACCGTTACCTCTTC-3'. Primers to amplify cDNA of HO-1 were 5'-GGGTGACAGAAGAGGCTAAG-3' and 5'-GTGTCTGGGATGAGCTAGTG-3'. Primers to amplify cDNA of hypoxanthine phosphoribosyl-transferase (HPRT), a house keeping gene, were 5'-CTCGAAGTGTTGGATACAGG-3' and 5'-AACTTGCGCTCATCTTAGG-3'.
Determination of HO activity
HO activity in microsomes was determined in LV tissues as previously described (Imai et al. 2001). The activity was expressed as nmol bilirubin formed per hour per mg of protein. The protein concentration was determined by a dye binding assay (Bio-Rad).
Immunohistochemistry
Immunohistochemical analyses of HO-1, endothelium, smooth muscle cells and monocytes were performed in frozen and paraffin sections. Sections were incubated overnight at 4 °C with a 1 : 500 dilution of a polyclonal rabbit anti-HO-1 antibody (Stressgen), a 1 : 200 dilution of a polyclonal rat anti-CD31 antibody (BD Pharmingen) for the endothelium, a 1 : 200 dilution of a monoclonal anti--smooth muscle actin (-SM) antibody (DAKO, clone 1A4) for vascular smooth muscle cells and a 1 : 200 dilution of a monoclonal anti-CD68 antibody (Serotec) for monocytes. Signals for HO-1, CD31 and -SM were visualized by the avidin-biotin immunoperoxidase method (ABC Elite kit, Vector Laboratories) using diaminobentizin as a substrate. Signals for CD68 were visualized using alkaline phosphatase as a substrate (Vector Laboratories).
The volume of vascular smooth muscle layer was quantified by morphometry in the LV sections stained with -smooth muscle actin. The digital images were analyzed using Scion Image software program, in which the areas of outer and inner profiles of intracardiac arteries were calculated and the difference was regarded as the vascular area. We examined slides from 5 Bach1–/– mice and 5 Bach1+/+ mice (sham-operated groups).
In situ detection of apoptosis
Apoptotic myocardial cells were detected in paraffin sections by the TUNEL technique with ApopTag‘ Plus (Invitrogen) according to the manufacturer's instructions. Since most of the TUNEL positive cells are observed in the ischemic region of LV, we evaluated only the ischemic myocardium in the sections. We estimated the perfusion area of LAD, i.e. the ischemic LV region, by macro anatomy in reference to right ventricle, and the border was marked on the slides with a marker. The labels of slides were blinded and sections of sham-operated animals were similarly examined. We sampled ten microscopic fields (at x1000 magnification) within the ischemic LV region avoiding overlap. This policy invariably resulted in examining most of the ischemic region of LV. The numbers of TUNEL-positive and negative cells were counted in each field and the percentage of TUNEL-positive cells was calculated, then the data from the ten fields were averaged. Each field contained approximately 50–70 cells including cardiomyocytes and non-myocytes. Cardiomyocytes were distinguished from non-myocytes by microscopic appearance; that is, well-shaped, elongated, and striated cells. We examined slides from 5 Bach1–/– mice and 5 Bach1+/+ mice (I/R groups).
Statistical analysis
All results are expressed as mean ± SEM. Comparison between two groups was made by Student's t-test, and comparison among four or five groups was made by analysis of variance followed by Scheffe's posthoc analysis. Statistical significance was accepted at a value of P < 0.05.
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Acknowledgements |
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Footnotes |
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aPresent address: Department of Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo, Aoba-ku, Sendai 980-8575, Japan
* Correspondence: E-mail: ozono{at}hiroshima-u.ac.jp |
References |
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TopAbstractIntroductionResultsDiscussionExperimental proceduresReferences |
|---|
Amersi, F., Buelow, R., Kato, H., et al. (1999) Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. J. Clin. Invest. 104, 1631–1639.[Medline]
Blydt-Hansen, T.D., Katori, M., Lassman, C., et al. (2003) Gene transfer-induced local heme oxygenase-1 overexpression protects rat kidney transplants from ischemia/reperfusion injury. J. Am. Soc. Nephrol.
14, 745–754.
Hangaishi, M., Ishizaka, N., Aizawa, T., et al. (2000) Induction of heme oxygenase-1 can act protectively against cardiac ischemia/reperfusion in vivo. Biochem. Biophys. Res. Commun. 279, 582–588.[CrossRef][Medline]
Harada, M., Qin, Y., Takano, H., et al. (2005) G-CSF prevents cardiac remodeling after myocardial infarction by activating the Jak-Stat pathway in cardiomyocytes. Nat. Med. 11, 305–311.[CrossRef][Medline]
Hilfiker-Kleiner, D., Hilfiker, A., Fuchs, M., et al. (2004) Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury. Circ. Res.
95, 187–195.
Imai, T., Morita, T., Shindo, T., et al. (2001) Vascular smooth muscle cell-directed overexpression of heme oxygenase-1 elevates blood pressure through attenuation of nitric oxide-induced vasodilation in mice. Circ. Res.
89, 55–62.
Ishii, T., Itoh, K., Takahashi, S., et al. (2000) Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J. Biol. Chem.
275, 16023–16029.
Itoh, K., Chiba, T., Takahashi, S., et al. (1997) An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem. Biophys. Res. Commun. 236, 313–322.[CrossRef][Medline]
Jacoby, J.J., Kalinowski, A., Liu, M.G., et al. (2003) Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age. Proc. Natl. Acad. Sci. USA
100, 12929–12934.
Juan, S.H., Lee, T.S., Tseng, K.W., et al. (2001) Adenovirus-mediated heme oxygenase-1 gene transfer inhibits the development of atherosclerosis in apolipoprotein E-deficient mice. Circulation
104, 1519–1525.
Kaiser, R.A., Bueno, O.F., Lips, D.J., et al. (2004) Targeted inhibition of p38 mitogen-activated protein kinase antagonizes cardiac injury and cell death following ischemia-reperfusion in vivo. J. Biol. Chem.
279, 15524–15530.
Kataoka, K., Handa, H. & Nishizawa, M. (2001) Induction of cellular antioxidative stress genes through heterodimeric transcription factor Nrf2/small Maf by antirheumatic gold(I) compounds. J. Biol. Chem.
276, 34074–34081.
Kobayashi, M. & Yamamoto, M. (2005) Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation. Antioxid. Redox Signal. 7, 385–394.[CrossRef][Medline]
Kukielka, G.L., Smith, C.W., Manning, A.M., Youker, K.A., Michael, L.H. & Entman, M.L. (1995) Induction of interleukin-6 synthesis in the myocardium. Potential role in postreperfusion inflammatory injury. Circulation
92, 1866–1875.
Kunisada, K., Hirota, H., Fujio, Y., et al. (1996) Activation of JAK-STAT and MAP kinases by leukemia inhibitory factor through gp130 in cardiac myocytes. Circulation
94, 2626–2632.
Ma, X.L., Kumar, S., Gao, F., et al. (1999) Inhibition of p38 mitogen-activated protein kinase decreases cardiomyocyte apoptosis and improves cardiac function after myocardial ischemia and reperfusion. Circulation
99, 1685–1691.
Mackay, K. & Mochly-Rosen, D. (1999) An inhibitor of p38 mitogen-activated protein kinase protects neonatal cardiac myocytes from ischemia. J. Biol. Chem.
274, 6272–6279.
Maekawa, N., Wada, H., Kanda, T., et al. (2002) Improved myocardial ischemia/reperfusion injury in mice lacking tumor necrosis factor-. J. Am. Coll. Cardiol.
39, 1229–1235.
Melo, L.G., Agrawal, R., Zhang, L., et al. (2002) Gene therapy strategy for long-term myocardial protection using adeno-associated virus-mediated delivery of heme oxygenase gene. Circulation
105, 602–607.
Negoro, S., Kunisada, K., Tone, E., et al. (2000) Activation of JAK/STAT pathway transduces cytoprotective signal in rat acute myocardial infarction. Cardiovasc. Res.
47, 797–805.
Ogawa, K., Sun, J., Taketani, S., et al. (2001) Heme mediates derepression of Maf recognition element through direct binding to transcription repressor Bach1. EMBO J. 20, 2835–2843.[CrossRef][Medline]
Oishi, Y., Ozono, R., Yano, Y., et al. (2003) Cardioprotective role of AT2 receptor in postinfarction left ventricular remodeling. Hypertension
41, 814–818.
Omura, S., Suzuki, H., Toyofuku, M., Ozono, R., Kohno, N. & Igarashi, K. (2005) Effects of genetic ablation of bach1 upon smooth muscle cell proliferation and atherosclerosis after cuff injury. Genes Cells
10, 277–285.
Otterbein, L.E., Kolls, J.K., Mantell, L.L., Cook, J.L., Alam, J. & Choi, A.M. (1999) Exogenous administration of heme oxygenase-1 by gene transfer provides protection against hyperoxia-induced lung injury. J. Clin. Invest. 103, 1047–1054.[Medline]
Oyake, T., Itoh, K., Motohashi, H., et al. (1996) Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site. Mol. Cell. Biol.
16, 6083–6095.
Pennica, D., King, K.L., Shaw, K.J., et al. (1995) Expression cloning of cardiotrophin 1, a cytokine that induces cardiac myocyte hypertrophy. Proc. Natl. Acad. Sci. USA
92, 1142–1146.
Poss, K.D. & Tonegawa, S. (1997) Reduced stress defense in heme oxygenase 1-deficient cells. Proc. Natl. Acad. Sci. USA
94, 10925–10930.
Sheng, Z., Knowlton, K., Chen, J., Hoshijima, M., Brown, J.H. & Chien, K.R. (1997) Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophy. J. Biol. Chem.
272, 5783–5791.
Stephanou, A. (2004) Role of STAT-1 and STAT-3 in ischaemia/reperfusion injury. J. Cell. Mol. Med. 8, 519–525.[Medline]
Stocker, R., Yamamoto, Y., McDonagh, A.F., Glazer, A.N. & Ames, B.N. (1987) Bilirubin is an antioxidant of possible physiological importance. Science
235, 1043–1046.
Sun, J., Brand, M., Zenke, Y., Tashiro, S., Groudine, M. & Igarashi, K. (2004) Heme regulates the dynamic exchange of Bach1 and NF-E2-related factors in the Maf transcription factor network. Proc. Natl. Acad. Sci. USA
101, 1461–1466.
Sun, J., Hoshino, H., Takaku, K., et al. (2002) Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene. EMBO J. 21, 5216–5224.[CrossRef][Medline]
Suzuki, H., Tashiro, S., Hira, S., et al. (2004) Heme regulates gene expression by triggering Crm1-dependent nuclear export of Bach1. EMBO J. 23, 2544–2553.[CrossRef][Medline]
Suzuki, H., Tashiro, S., Sun, J., Doi, H., Satomi, S. & Igarashi, K. (2003) Cadmium induces nuclear export of Bach1, a transcriptional repressor of heme oxygenase-1 gene. J. Biol. Chem.
278, 49246–49253.
Tongers, J., Fiedler, B., Konig, D., et al. (2004) Heme oxygenase-1 inhibition of MAP kinases, calcineurin/NFAT signaling, and hypertrophy in cardiac myocytes. Cardiovasc. Res.
63, 545–552.
Tulis, D.A., Durante, W., Liu, X., Evans, A.J., Peyton, K.J. & Schafer, A.I. (2001) Adenovirus-mediated heme oxygenase-1 gene delivery inhibits injury-induced vascular neointima formation. Circulation
104, 2710–2715.
Vulapalli, S.R., Chen, Z., Chua, B.H., Wang, T. & Liang, C.S. (2002) Cardioselective overexpression of HO-1 prevents I/R.-induced cardiac dysfunction and apoptosis. Am. J. Physiol. Heart Circ. Physiol.
283, H688–H694.
Xuan, Y.T., Guo, Y., Han, H., Zhu, Y. & Bolli, R. (2001) An essential role of the JAK-STAT pathway in ischemic preconditioning. Proc. Natl. Acad. Sci. USA
98, 9050–9055.
Yet, S.F., Tian, R., Layne, M.D., et al. (2001) Cardiac-specific expression of heme oxygenase-1 protects against ischemia and reperfusion injury in transgenic mice. Circ. Res.
89, 168–173.
Received: 22 December 2005
Accepted: 10 April 2006
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P < 0.05 vs. I/R (n-isc) groups of each mouse group, ¶P < 0.05 vs. I/R (n-isc) group in the other two mouse groups, 
P < 0.05 vs. I/R (isc) group in the other two mouse groups.
