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Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan (K.-I.T., S.T., Y.A., T.H., K.S., T.I., T.M.); Department of Biochemistry and Molecular Biology, Yamaguchi University School of Medicine, Ube, Japan (E.T., A.N.); and Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Kyoto, Japan (K.T.)
Received December 7, 2006; accepted December 22, 2006
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Abstract |
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). To protect the gastric mucosa, a complex defense system, which includes the production of surface mucus and bicarbonate and the regulation of gastric mucosal blood flow (GMBF), has evolved. Prostaglandins (PGs), in particular PGE2, enhance these protective mechanisms and are therefore believed to comprise a major gastric mucosal defensive factor (Miller, 1983).
Heat shock proteins (HSPs) have also attracted considerable attention as another major defensive factor. When cells are exposed to stressors, a number of so-called stress proteins are induced to confer protection against such stressors. HSPs are representative of these stress proteins, and their cellular up-regulation, especially that of HSP70, provides resistance as they refold or degrade denatured proteins produced by the stressors (Gething and Sambrook, 1992; Jaattela et al., 1998; Kiang and Tsokos, 1998; Mathew and Morimoto, 1998; Jaattela, 1999; Beere et al., 2000; Saleh et al., 2000; Ravagnan et al., 2001). It has been reported not only that various gastric irritants, including ethanol, up-regulate HSPs, but also that artificial up-regulation of HSPs confers resistance to these irritants in cultured gastric mucosal cells (Nakamura et al., 1991; Hirakawa et al., 1996; Mizushima et al., 1999; Saika et al., 2000; Tomisato et al., 2000, 2001). Similar up-regulation of HSPs by gastric irritants has also been recorded in vivo, in addition to which whole-body heat treatment has been shown to suppress gastric irritant-induced lesions (Zeniya et al., 1995; Otani et al., 1997; Itoh and Noguchi, 2000; Saika et al., 2000). Although these findings strongly indicate that HSPs are protective, very little direct evidence exists, and to date, no in vivo study has been conducted to demonstrate that inhibition of HSPs results in a phenotype susceptible to irritant-induced gastric lesions.
It is interesting that geranylgeranylacetone (GGA), a leading antiulcer drug on the Japanese market, has been reported to be a nontoxic HSP-inducer, up-regulating various HSPs not only in cultured gastric mucosal cells at concentrations that do not affect cell viability but also in various tissues, including the gastric mucosa in vivo (Hirakawa et al., 1996; Ooie et al., 2001; Katsuno et al., 2005; Yasuda et al., 2005). We have reported previously that preinduction of HSPs by GGA protects cultured gastric mucosal cells from cell death induced by various irritants, including ethanol, hydrochloric acid, hydrogen peroxide, and NSAIDs (Mizushima et al., 1999; Tomisato et al., 2000, 2001; Takano et al., 2002). These previous results suggest that the antiulcer effect of GGA is due to its HSP-inducing activity. However, because GGA mediates various other gastroprotective mechanisms, such as an increase in GMBF, stimulation of surface mucus production, and direct protection of gastric mucosal cell membranes (Terano et al., 1986; Kunisaki and Sugiyama, 1992; Ushijima et al., 2005), it remains unclear whether up-regulation of HSPs represents GGA's major mode of antiulcer activity.
The up-regulation of HSPs by various stressors, including heat shock, is regulated at the transcription level by a consensus cis-element (heat shock element) and a transcription factor (HSF1) that specifically binds to heat shock element located on the upstream region of hsp genes (Morimoto, 1998). The essential role of HSF1 in the up-regulation of HSPs, conferring cytoprotection against stressors, was demonstrated by the observation that disruption of the activity of HSF1 leads to the loss of stressor-induced HSP up-regulation and the emergence of cells that are sensitive to apoptosis (McMillan et al., 1998; Morimoto, 1998). Furthermore, analysis of HSF1-null mice revealed that up-regulation of HSPs is involved in various physiological and pathological phenomena, suggesting that HSF1-null mice provide a powerful tool for examination of the role of HSPs in vivo (Xiao et al., 1999; Christians et al., 2000; Yan et al., 2002). In this study, we used the HSF1-null mouse model to obtain direct genetic evidence for the contribution of HSPs to the protection of the gastric mucosa. We also investigated whether up-regulation of HSPs by GGA contributes to its antiulcer activity.
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Materials and Methods |
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), and both mice of 10 to 12 weeks of age and 25 to 30 g were used in experiments. The experiments and procedures described here were carried out in accordance with the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the National Institutes of Health (Bethesda, MD) and were approved by the Animal Care Committee of Kumamoto University.
Gastric Damage Assay. Gastric ulcerogenic response was examined as described previously (Tomisato et al., 2004), with some modifications. Mice, which had been fasted for 24 h, were orally administered either ethanol or hydrochloric acid (5 ml/kg). Four hours later, the animals were sacrificed with an overdose of ether, after which their stomachs were removed and scored for hemorrhagic damage by an observer unaware of the treatment they had received. Calculation of the scores involved measuring the area of all lesions in square millimeters and summing the values to give an overall gastric lesion index. Gastric mucosal PGE2 levels were determined by ELISA as described previously (Futaki et al., 1993).
Cell Culture, Overexpression, and siRNA Targeting of HSP70. Human gastric carcinoma (AGS) cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum, 100 U/ml penicillin, and 100 µg/ml streptomycin in a humidified atmosphere of 95% air with 5% CO2 at 37°C. Cells were exposed to ethanol by changing the medium. Cells were cultured for 24 h and were used in experiments. Cell viability was determined by the MTT method. The transfection with pcDNA3.1 containing the hsp70 gene (Fujimoto et al., 2005) was carried out using Lipofectamine (TM2000) according to the manufacturer's instructions. Cells were used for experiments after an 18-h recovery period.
We used siRNA of 5'-ggagcuggagcaggugugudTdT-3' and 5'-acacaccugcuccagcuccdTdT-3' as annealed oligonucleotides for repressing HSP70 expression. AGS cells were transfected with siRNA using RNAiFect transfection reagent according to the manufacturer's instructions. Nonsilencing siRNA (5'-uucuccgaacgugucacgudTdT-3' and 5'-acgugacacguucggagaadTdT-3') was used as a negative control.
Real-Time RT-PCR Analysis. Total RNA was extracted from the gastric mucosa using an RNeasy kit according to the manufacturer's protocols. Samples (10 µg of RNA) were reverse-transcribed using a first-strand cDNA synthesis kit according to the manufacturer's instructions. Synthesized cDNA (15 ng) was applied to real-time RT-PCR (Prism 7700; Applied Biosystems, Foster City, CA) using SYBR GREEN PCR Master Mix and analyzed with ABI Prism 7700 Sequence Detection software according to the manufacturer's instructions. Real-time cycle conditions were 2 min at 50°C followed by 10 min at 90°C and finally 45 cycles at 95°C for 30 s and 63°C for 60 s. Specificity was confirmed by electrophoretic analysis of the reaction products and by inclusion of template- or reverse transcriptase-free controls. To normalize the amount of total RNA present in each reaction, the gene of glyceraldehyde-3-phosphate dehydrogenase was used as an internal standard.
Primers were designed using the Primer3 website (http://frodo.wi.mit.edu/cgi-bin/primer3/primer3_www.cgi). Primers are listed in Table 1.
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Immunoblotting Analysis. Total protein was extracted from the gastric mucosa as described previously (Tsutsumi et al., 2002). The protein concentration of the samples was determined by the Bradford method. Samples were applied to 8% (HSP70 and HSP90), 10% (HSP60 and actin), or 12% (HSP25) polyacrylamide SDS gels and subjected to electrophoresis, after which the proteins were immunoblotted with appropriate antibodies.
Histological and Immunohistochemical Analysis. Gastric tissue samples were fixed in 4% buffered paraformaldehyde, embedded in OCT compound, and cryosectioned. Sections were stained first with Mayer's hematoxylin and then with 1% eosin alcohol solution for histological examination [hematoxylin and eosin (HE) staining]. Samples were mounted with malinol and inspected using an Olympus IX70 microscope (Olympus, Tokyo, Japan).
For immunohistochemical analysis, sections were blocked with 2.5% goat serum for 10 min, incubated for 12 h with antibody against HSP70 (1:200 dilution) in the presence of 2.5% BSA, and finally incubated for 1 h with Alexa Fluor 488 (or 594) goat antimouse immunoglobulin G in the presence of DAPI (5 µg/ml). Samples were mounted with Vectashield and inspected using fluorescence microscopy (Olympus IX70).
TdT-Mediated dUTP-Biotin End Labeling Assay. Gastric tissue samples were fixed in 4% buffered paraformaldehyde, embedded in OCT compound, and cryosectioned. Sections were incubated first with proteinase K (10 µg/ml) for 15 min at 37°C, then with terminal deoxynucleotidyl transferase and biotin 14-ATP for 1 h at 37°C, and finally with Alexa Fluor 488 conjugated with streptavidin for 1 h. Samples were mounted with Vectashield and inspected using fluorescence microscopy (Olympus IX70).
Measurement of Gastric Acid Secretion and GMBF. Gastric acid secretion was measured as described previously (Filaretova et al., 2002), with some modifications. Under ether anesthesia, the abdomen was opened, and the pylorus was ligated. After drug administration, mice were sacrificed, and their stomachs were removed. The gastric contents were collected and titrated with 10 mM NaOH to pH 7.0 using an automatic titrator (TITRONIC basis; Schott, Roseville, CA).
GMBF was measured as described elsewhere (Takeuchi et al., 2003), with some modifications. Under urethane-anesthetized conditions, the stomach was exposed and mounted in an ex vivo chamber. GMBF was measured with a laser Doppler flowmeter (ALF-21; Advance, Tokyo, Japan).
Statistical Analysis. All values are expressed as the mean ± standard error (S.E.M.). Two-way analysis of variance followed by Scheffe's multiple comparison test or Tukey test was used for evaluation of differences between groups. The Student's t test for unpaired results was used for the evaluation of differences between two groups. Differences were considered to be significant for values of P < 0.05.
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Results |
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Ethanol-Induced Up-Regulation of HSPs in Gastric Mucosa. Given that HSF1 up-regulates the expression of HSPs at the transcriptional level, we examined the effect of ethanol administration on the expression of hsp mRNAs and HSPs in the gastric mucosa of HSF1-null mice and wild-type mice. Figure 2A shows the level of various hsp mRNAs that were detected by real-time RT-PCR. Lack of the hsf1 gene did not affect the background level of expression of hsp mRNAs, as reported previously (McMillan et al., 1998; Xiao et al., 1999; Inouye et al., 2003). Ethanol administration up-regulated the level of hsp25, hsp70, and hsp90
but not hsp60 and hsp90
mRNA in wild-type mice (Fig. 2A). This up-regulation was not observed in HSF1-null mice (Fig. 2A). Among hsp25, hsp70, and hsp90 mRNAs, the hsp70 mRNA displayed the strongest HSF1-dependent up-regulation induced by ethanol (Fig. 2A).
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Figure 2B shows the protein level of various HSPs as assessed by the immunoblotting assay. Unlike the results of the mRNA analysis (Fig. 2A), lack of the hsf1 gene caused a decrease in the background expression level of HSP25, HSP60, HSP70, and HSP90 (Fig. 2B). This is the first examination of the background expression level of HSPs in stomach of HSF1-null mice, and results were consistent with previous data in other organs and cell species of HSF1-null mice, such as liver, fibroblasts, and dendritic cells (Xiao et al., 1999; Zheng and Li, 2004). Ethanol administration up-regulated the production of only HSP70, a response that was dependent on the function of HSF1 (Fig. 2B). Being different from results in mRNA level (Fig. 2A), the protein level of HSP25 and HSP90 was not up-regulated by the ethanol administration (Fig. 2B) and we have no clear explanation for this discrepancy at present. Based on the results illustrated in Fig. 2, together with those of a previous study suggesting that, among the HSPs, HSP70 plays a major role in cytoprotection (Gething and Sambrook, 1992; Jaattela et al., 1998; Mathew and Morimoto, 1998; Jaattela, 1999; Beere et al., 2000; Saleh et al., 2000; Ravagnan et al., 2001), we subsequently focused on HSP70.
To examine the ethanol-dependent up-regulation of HSP70 in the gastric mucosa in detail, we performed histological and immunohistochemical analyses. Sections were prepared from the gastric tissues of HSF1-null and wild-type mice that had been exposed to ethanol. HE and DAPI staining shows the presence of gastric mucosal lesions in both HSF1-null mice (with both 40 and 100% ethanol administration) and wild-type mice (with only 100% ethanol administration) (Fig. 3), and this is consistent with the results illustrated in Fig. 1B. Furthermore, immunohistochemical analysis with an antibody against HSP70 demonstrated that HSP70 is induced by the administration of 100% ethanol in wild-type mice and that this up-regulation is most apparent in the vicinity of gastric lesions (Fig. 3A), suggesting that HSP70 induced by ethanol plays an important role in development of gastric lesions. In contrast, no significant up-regulation of HSP70 was observed in HSF1-null mice after administration of either 40% or 100% ethanol (Fig. 3B). This pattern of HSP70 expression is consistent with the results illustrated in Fig. 2B. Together, the results outlined in Figs. 2 and 3 show that the induction HSP70 in the gastric mucosa after oral administration of ethanol is dependent on HSF1 function.
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). Administration of 40% ethanol did not affect gastric acid secretion in either wild-type or HSF1-null mice (Fig. 6B). Similar results were obtained with 100% ethanol (data not shown). Furthermore, both the background level of gastric acid secretion and that recorded after administration of 40% ethanol were not significantly affected by the lack of the hsf1 gene (Fig. 6B). These results suggest that the stimulation of ethanol-induced gastric lesion production in HSF1-null mice does not involve a change in gastric acid secretion.
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GMBF is another important factor in the production of gastric lesions, with a decrease in GMBF having a causative effect. As shown in Fig. 6C, GMBF in wild-type mice was stimulated by the addition of PGE2, as described previously (Araki et al., 2000). However, no significant difference in GMBF was recorded between wild-type and HSF1-null mice (Fig. 6C), indicating that HSF1 does not affect GMBF.
As described above, PGE2 is a major defensive factor for the gastric mucosa, exerting a protective effect against various irritants by decreasing gastric acid secretion and increasing GMBF, in addition to other mechanisms (Miller, 1983). Therefore, as the results illustrated in Fig. 6, A to C, suggest, it is unlikely that aggravation of ethanol-induced gastric lesions in HSF1-null mice involves PGE2. To confirm this, we examined the effect of ethanol on gastric mucosal PGE2 levels in wild-type and HSF1-null mice. As shown in Fig. 6D, ethanol administration did not affect the level of PGE2 in either group of animals. Furthermore, there was no significant difference in PGE2 levels between wild-type and HSF1-null mice in either the presence or absence of ethanol treatment (Fig. 6D). These results support the idea that stimulation of ethanol-induced gastric lesions in HSF1-null is not attributable to the impairment of PGE2 production.
Antiulcer and HSP-Inducing Activities of GGA in HSF1-Null Mice. To evaluate the contribution of the HSP-inducing activity of GGA to its antiulcer activity, we investigated the effect of GGA in HSF1-null mice. First, we examined the effect of GGA and/or ethanol on gastric mucosal HSP70 expression in wild-type mice, revealing a potent expression induced by ethanol and a lower level of expression in response to GGA (Fig. 7A). It is interesting that preadministration of GGA enhanced the ethanol-dependent HSP70 response (Fig. 7A). Figure 7C shows the effect of preadministration of GGA on ethanol-produced gastric lesions in wild-type and HSF1-null mice. To obtain similar levels of gastric lesions, 100 and 40% ethanol administration were administered to wild-type and HSF1-null mice, respectively. In fact, 40% ethanol administration in HSF1-null mice caused a comparable lesion score as 100% ethanol administration in wild-type mice (Fig. 7C). Preadministration of GGA significantly suppressed the ethanol-dependent production of gastric lesions in wild-type mice (Fig. 7C), as described previously (Murakami et al., 1981). In contrast, no significant effect was recorded in the HSF1-null mice (Fig. 7C). We confirmed that administration of GGA and/or 40% ethanol did not induce HSP70 (Fig. 7B). This result shows that HSF1 is required for the efficacy of the antiulcer activity of GGA against ethanol. Overall, the results in Fig. 7 suggest that the loss of the protective effect of GGA in HSF1-null mice is due to the lack of expression of HSPs (such as HSP70); in other words, the HSP-inducing activity of GGA contributes to its antiulcer activity.
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Discussion |
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; Hirakawa et al., 1996; Mizushima et al., 1999; Tomisato et al., 2000, 2001; Takano et al., 2002), whereas exposure to such irritants induces HSP production (Zeniya et al., 1995; Otani et al., 1997; Itoh and Noguchi, 2000; Saika et al., 2000). In this study, we found that HSF1-null mice are more susceptible to irritant-induced gastric lesions, providing direct genetic evidence for the significance of HSPs in amelio-rating the outcome of irritant-induced gastric insults. Further genetic evidence in support of this notion has recently been published, revealing that transgenic mice overexpressing human HSP27 display a phenotype that is resistant to NSAID-induced gastric lesions (Ebert et al., 2005).
Based on our results, we believe that the production of gastric lesions in HSF1-null mice is due to their inability to express protective HSPs, leading to apoptosis of the gastric mucosal cells. Although oral administration of ethanol led to the production of gastric lesions, there was a concomitant up-regulation of HSPs (Figs. 2 and 3), with significantly fewer apoptotic cells being recorded in wild-type mice than in HSF1-null mice (Fig. 4). Induction of necrosis by ethanol may also be stimulated in HSF1-null mice, because up-regulation of HSPs made gastric mucosal cells resistant to ethanol-induced necrosis (Tomisato et al., 2001). Other factors that are believed to be involved in the production of gastric lesions, including gastric acid secretion, GMBF, and PGE2 levels, were similar in both wild-type and HSF1-null mice (Fig. 6). Artificial preinduction of HSPs renders cultured gastric mucosal cells resistant to ethanol-induced apoptosis (Mizushima et al., 1999). Among the various HSPs tested, oral administration of ethanol up-regulated only HSP70 in terms of protein level (Fig. 2B). Furthermore, HSP70 is believed to be the major antiapoptotic HSP; either HSP70 binds to Apaf-1, thereby preventing activation of caspases, or HSP70 suppresses the apoptotic pathway downstream of caspase-3 activation and apoptosis-inducing factor-induced chromatin condensation (Jaattela et al., 1998; Beere et al., 2000; Saleh et al., 2000; Ravagnan et al., 2001). However, despite the apparent significance of HSP70, it should still be noted that loss of the hsf1 gene also decreased the background level of other HSPs (Fig. 2B), which may play some role in the HSF1-dependent protection of the gastric mucosa. It is also possible that the production of gastric lesions in HSF1-null mice involves other mechanisms, suggested in recent articles (Inouye et al., 2003; Fujimoto et al., 2005). For example, HSF1-null mice display elevated levels of tumor necrosis factor (TNF)-, a proinflammatory cytokine, and are susceptible to increased mortality after endotoxic or inflammatory challenge (Xiao et al., 1999; Wirth et al., 2004). Given that it is well-known that proinflammatory cytokines, including TNF-, stimulate the production of gastric lesions, it remains possible that the development of such lesions in HSF1-null mice involves elevated levels of TNF-. In addition, involvement of iNOS is also possible, because it has been shown that iNOS is involved in tissue damage, and overexpression of HSP70 has been shown to inhibit iNOS and ameliorate the damage (Pittet et al., 2002; Kiang, 2004).
GGA has attracted considerable attention as an HSP-inducer, largely because of its clinical value as an antiulcer drug and because it can induce HSPs without affecting cell viability (Hirakawa et al., 1996). GGA has been suggested to play a protective role through HSP induction in a variety of disease states; oral administration of GGA up-regulates HSPs in brain and heart and exerts a protective effect against spinal and bulbar muscular atrophy, cerebral ischemia, and ischemic heart disease (Ooie et al., 2001; Katsuno et al., 2005; Yasuda et al., 2005). However, no previous reports have shown that the HSP-inducing activity of GGA contributes to these clinically beneficial outcomes, including its antiulcer effects. In this study, using immunohistochemical analysis, we have demonstrated that oral administration of GGA alone up-regulates gastric mucosal HSP70 and that preadministration of GGA stimulates the ethanol-induced up-regulation of HSP70. Furthermore, we have revealed that preadministration of GGA suppresses gastric lesions in wild-type mice but not in HSF1-null mice. These results argue strongly in favor of the HSP-inducing activity of GGA contributing to its antiulcer effects, providing the first direct genetic link between the pharmacological behavior of the drug and the resultant clinical outcome. In summary, this study provides direct genetic evidence suggesting that HSPs, after their HSF1-dependent up-regulation, confer protection against the development of gastric lesions.
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Footnotes |
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K.T. and S.T. contributed equally to this work.
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS: NSAID, nonsteroidal anti-inflammatory drug; DAPI, 4', 6-diamidino-2-phenylindole dihydrochloride; GGA, geranylgeranylacetone; GMBF, gastric mucosal blood flow; HE, hematoxylin and eosin; HSF, heat shock factor; HSP, heat shock protein; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; OCT, optimal cutting temperature; PG, prostaglandin; TNF, tumor necrosis factor; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling; HSF1, heat shock factor 1; ELISA, enzyme-linked immunosorbent assay; siRNA, short interfering RNA; AGS, human gastric carcinoma; iNOS, inducible nitric-oxide synthase; RT-PCR, reverse transcription-polymerase chain reaction.
Address correspondence to: Dr. Tohru Mizushima, Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-honmachi, Kumamoto 862-0973, Japan. E-mail: mizu{at}gpo.kumamoto-u.ac.jp
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