(Hypertension. 1998;31:342.)
© 1998 American Heart Association, Inc.
Scientific Contributions |
Downregulation of Angiotensin II Type 1 Receptor Gene Transcription by Nitric Oxide
From Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University, School of Medicine, Fukuoka, Japan.
Correspondence to Toshihiro Ichiki, MD, Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University, School of Medicine, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-82, Japan. E-mail ichiki{at}cardiol.med.kyushu-u.ac.jp
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Abstract |
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Nitric oxide (NO) plays an important role not only in the regulation of blood vessel tone, but also in the growth of vascular smooth muscle cells (VSMC). The precise mechanism involved in the inhibition of VSMC growth by NO is not known. To further explore the effect of NO on VSMC growth, we examined the effect of NO on the expression of angiotensin II type 1 receptor (AT1-R) that is important for hypertrophy and hyperplasia of VSMC. S-nitroso acetyl DL-penicillamine (SNAP; 200µmol/L), a potent NO donor, suppressed expression level of AT1-R mRNA by 90% and AT1-R number by 60% after 24 hours of stimulation. The suppressive effect was dose-dependent. Actinomycin D, which is an inhibitor of gene transcription, did not affect the decrease of AT1-R mRNA by NO. Cyclic guanosine monophosphate (cGMP) analogue, 8 bromo-cGMP, did not affect AT1-R mRNA level. Deletion mutants of the promoter region of rat AT1a-R gene were fused to luciferase reporter gene and introduced to VSMC. Transfected cells were stimulated with SNAP, and luciferase activity was measured. Inhibitory effect of NO was still observed in the shortest deletion mutant that contained 61 bp upstream from transcription start site. In this DNA segment, two DNA binding protein were observed by gel mobility shift assay, and one of these binding proteins was decreased on stimulation by NO. NO downregulates AT1-R gene expression independently of cGMP. A DNA binding protein that binds to the proximal promoter region of AT1-R gene may be responsible for this inhibitory effect. The inhibition of AT1-R gene expression may be implicated in the anti-atherogenic property of NO.
Key Words: vascular smooth muscle cells • angiotensin II receptor • NO • gene transcription
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Introduction |
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Proliferation of vascular smooth muscle cells (VSMC) contributes to pathological changes of vascular wall such as vascular remodeling, medial hyperplasia, and neointimal formation associated with hypertension, atherosclerosis, and vascular injury.1 In addition, VSMC produce matrix component of vascular wall such as collagen, fibronectin, and growth factors such as platelet-derived growth factor (PDGF). The matrix and growth factors also play important roles in the process of vascular remodeling and atherogenesis. Therefore, understanding the mechanism of VSMC proliferation is of great interest in vascular biology and clinical investigation.
Nitric oxide (NO) is produced by a variety of mammalian cells such as endothelium, neuron, macrophages, and VSMC from L-arginine by NO synthase (NOS).2,3 Release of NO stimulates soluble guanylyl cyclase, leading to an increase of intracellular cyclic guanosine monophosphate (cGMP) level. NO dilates blood vessel and inhibits proliferation of VSMC and platelet aggregation.3 These properties are anti-atherogenic, and decreased NOS activity is believed to be one of the important feature of early atherogenic process.2 Supplementation of L-arginine, the precursor of NO, lessens the extent of atherosclerosis in diet-induced hypercholesterolemic rabbit.4 In vivo transfer of type III NOS gene into the balloon-injured artery decreased neointimal VSMC proliferation.5 However, the precise mechanism of anti-atherogenic property of NO is not completely understood.
Angiotensin (Ang) II is an important vasoactive peptide and regulates blood pressure, fluid homeostasis, and electrolyte balance by vasoconstriction, facilitation of adrenergic nerve activity, and secretion of aldosterone from the adrenal gland.6,7 Recent studies have shown that Ang II is a growth factor of VSMC and endothelium and plays an important role in atherosclerosis. The physiological function of Ang II is transmitted into target cells via its specific receptor located in the cell membrane. There are two isoforms for Ang II receptor, which are designated as type 1 receptor (AT1-R)8,9 and type 2 receptor (AT2-R).10,11 Losartan that binds to AT1-R and PD123319 that binds to AT2-R are considered to be isoform specific antagonist. Although emerging evidences suggest that AT2-R also plays an important role in the regulation of blood pressure,12 growth inhibition,13 and apoptosis,14 most of the cardiovascular effects of Ang II has been believed to be mediated by AT1-R.6,7 In rodents, two subtypes of AT1 receptor are cloned and named AT1a and AT1b.15 Cultured VSMC express only AT1a-R, and Ang II induces PDGF-A chain, transforming growth factor-ß and collagen synthesis in cultured VSMC via this receptor. These products from VSMC are important for remodeling of vascular wall and progression of atherosclerosis.
Several reports have shown that NO modulates biological function of Ang II such as Ang II-induced migration of VSMC16 or Ang II-induced cardiac fibrosis.17 We have also reported that chronic inhibition of nitric oxide synthesis by N
-nitro L-arginine methyl ester (L-NAME) activates the renin-angiotensin system and causes vascular remodeling of coronary arteries of the heart.18 However, it has not been determined whether NO affects the expression of Ang II receptor. In this study, we examined the effect of NO donor on the expression of AT1-R in cultured VSMC. We found that downregulation of AT1-R occurs at the transcription level, independent of cGMP. Reporter gene analysis using firefly luciferase gene suggested that proximal promoter region of AT1a-R gene was important for this suppressive effect of NO, and a DNA binding protein bound to this segment was decreased by NO treatment. These data suggest that biological effect of Ang II via AT1-R is enhanced when NO activity is decreased. Downregulation of AT1-R may be one of the important mechanisms of the anti-atherogenic property of NO.
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Materials and Methods |
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Reagents
Dulbecco’s modified Eagle’s medium (DMEM) and fetal bovine serum were purchased from GIBCO BRL. S-nitroso acetyl D,L-penicillamine (SNAP) and other chemical reagents were purchased from Wako Chemicals, otherwise mentioned specifically. [32P]
-dCTP, [32P]
-ATP, and [125I] Sar,1Ile8-Ang II (Sarile) were from Du-Pont NEN. Bovine serum albumin was purchased from Sigma Chemical Co.
Cell Culture
VSMC were isolated from the thoracic aorta of spontaneously hypertensive rats as described previously19 and maintained in DMEM supplemented with 10% fetal bovine serum at 37°C in a humidified atmosphere of 95% air, 5% CO2. Cells (5x105) were seeded in a 6-cm tissue culture dish and cultured in DMEM with 10% fetal bovine serum for 4 days. Then the medium was changed to DMEM supplemented with 0.1% bovine serum albumin. The cells were cultured for an additional 2 days and stimulated with SNAP for the indicated period in the text.
Northern Blot Analysis
Total RNA was prepared by acid guanidium-phenol-chloroform extraction method.20 Ten µg of total RNA was electrophoresed in a 1.0% agarose, 1.0% formaldehyde gel, transferred to Hybond N+ membrane (Amersham) by a capillary transfer method in 10xSSC (1xSSC is 300 mmol/L of NaCl and 30 mmol/L of Na citrate) buffer overnight. The membrane was cross-linked by a UV cross-linker (Spectronics Corporation). Prehybridization and hybridization were performed in a buffer containing 50% formamide, 5xSSC, 80mmol/L sodium phosphate (pH 7.5), 2xDenhardt solution, 1% SDS, and 100 µg/L of heat-denatured herring sperm DNA for 2 hours and 16 hours, respectively, at 42°C. An Eco RI fragment of the third exon of rat AT1a gene21 and ß-actin cDNA were labeled with 32P by a Prime It kit (Stratagene) and used as a probe after heat denaturation. The hybridized membrane was washed twice with 2xSSC for 5 minutes at room temperature, followed by two washes with 2xSSC/1% SDS for 30 minutes at 55°C. The membrane was then exposed to Kodak X-OMAT film at -70°C. The hybridized membrane was stripped by boiling in 0.5% SDS solution and hybridized to a 32P-labeled ß-actin probe to obtain reference for the amount of applied RNA. Autoradiography was scanned by a densitometer and analyzed by a computer program (Mac Scope, Mitani Co. Ltd.). After scanning of the autoradiography, an appropriate window to determine the density of the band was set. Specific density was determined by subtracting the density of blank lane from that of samples.
To analyze mRNA stability of AT1-R, actinomycin D (5 mg/L) was added after 3 hours of stimulation with SNAP (200 µmol/L). Cells were harvested after 3, 6, 12, and 24 hours of addition of actinomycin D, and the expression level of AT1-R mRNA was examined by Northern blot analysis.
Transfection of AT1 Promoter-Luciferase Fusion DNA Construct to VSMC
Deletion mutants of the promoter region of rat AT1a gene were previously described.22 Confluent VSMC were split by trypsin/EDTA solution, and 5x105 cells were prepared in a 6-cm tissue culture dish. After 48 hours, 5 µg of AT1 promoter-luciferase fusion DNA construct and 2 µg of ß-galactosidase gene driven by SV40 promoter-enhancer sequence were introduced to VSMC by DEAE Dextran method according to the manufacture’s instruction (Promega Corporation). The cells were cultured in DMEM with 10% FCS for 48 hours, washed twice with phosphate-buffered saline, and stimulated with 200 µmol/L of SNAP for 24 hours. Then the cells were lysed in 200 µL of lysis buffer (25 mmol/L Tris, pH 7.8, 2 mmol/L EDTA, 2 mmol/L DTT, 10% glycerol, and 1% Triton X-100). One hundred µL of lysate was used for luciferase activity assay in a Lumat luminometer (LB 9501, Berthold). The assay was started by adding 100 µL of 470 mmol/L luciferin to cell lysate, and integrated peak luminescence was determined over a 55-second window after a 5-second delay. The ß-galactosidase activity in the same sample was measured spectrophotometrically according to Sambrook et al23 and used to normalize the luciferase activity.
Estimation of AT1-R Number
The number of AT1 binding sites was estimated by binding of [125I]-Sarile in the presence of PD123319, an AT2 receptor-specific antagonist. Confluent VSMC in 24 well dishes were starved in serum-free medium for 48 hours and incubated with or without 200 µmol/L of SNAP for 24 hours. Then the cells were washed twice with ice-cold phosphate-buffered saline and incubated for 90 minutes at 4°C with various concentrations of [125I]-Sarile in an incubation buffer (50 mmol/L Tris-HCl, pH 7.5, 100 mmol/L NaCl, 5 mmol/L MgCl2, 2 g/L bovine serum albumin, 0.5 g/L bacitracin). Cells were washed three times with ice-cold PBS and solubilized in 0.75 mL of 1N NaOH. An aliquot (0.2 mL) was subjected to counting radioactivity.
Preparation of Nuclear Extracts and Gel Mobility Shift Assay
Cell extracts were prepared according to methods described by Dignam et al24 and Osborn et al.25 Cells were scraped off, washed in ice-cold PBS followed by ice-cold hypotonic buffer (buffer A: 10 mmol/L HEPES, pH 7.9, 1.5 mmol/L MgCl2, 10 mmol/L KCl, 0.5mmol/L PMSF, 0.5 mmol/L DTT), and then lysed for 10 minutes on ice in the buffer A containing 0.1% Nonident P-40. The lysates were centrifuged for 10 minutes at 10000g. The pelleted nuclei were suspended in lysis buffer(20 mmol/L HEPES, pH 7.9, 420 mmol/L NaCl, 1.5 mmol/L MgCl2, 0.2 mmol/L EDTA, 25% glycerol, 0. 5 mmol/L PMSF, 0.5 mmol/L DTT), incubated for 15 minutes at 4°C, and centrifuged for 10 minutes at 10000g. The supernatant was used as nuclear extracts.
DNA probe (AT1-R gene promoter: -61bp/+25bp) was dephosphorylated by calf intestinal alkaline phosphatase, labeled with 32P by using [32P]-ATP and T4 polynucleotide kinase, and purified by Sephadex G-50 column. Ten µg of nuclear extract was incubated with 1x105 cpm of labeled DNA probe and 2 µg of poly (dI-dC) in a buffer containing 10 mmol/L Tris-HCl, pH 7.5, 1 mmol/L EDTA, 4% glycerol, 100 mmol/L NaCl, 5 mmol/L DTT, 100 g/L bovine serum albumin for 15 minutes at room temperature(25°C). Then the samples were electrophoresed on 5% acrylamide/0.25 x TBE gel (1 x TBE: 90 mmol/L of tris borate, 2 mmol/L of EDTA). After electrophoresis, gels were dried and exposed to x-ray film at -70°C.
Statistics
Statistical analyses of the relative AT1-R mRNA expression were performed by using ANOVA and Duncan’s test if appropriate. Difference of dissociation constant (Kd) and AT1 receptor sites (Bmax) were compared by using unpaired Student’s t-test. Degradation of AT1-R mRNA was analyzed by two-way ANOVA. Data are shown as mean±SEM. P<0.05 was considered to be significant.
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SNAP Suppressed AT1-R mRNA and Receptor Number
Two species of AT1-R mRNA were observed in VSMC (Fig 1) as previously reported,9 both of which are considered to encode AT1-R. Stimulation of the VSMC with SNAP for 24 hours dose-dependently inhibited AT1-R mRNA expression as shown in Fig 1. The two mRNA species were suppressed equally. For the densitometric analysis, densities of both bands were taken into account. AT1-R mRNA level stimulated with 300 µmol/L of SNAP is about 8% of the control mRNA level (lane 4). Fig 1B summarizes the densitometric analysis of Northern blot analysis. Next we examined time course of AT1-R mRNA downregulation by using 200 µmol/L of SNAP. Decrease of AT1-R mRNA level began as early as 3 hours of stimulation with SNAP (Fig 2, lane 2), and about 7% of mRNA was present after 24 hours of stimulation compared with the control mRNA level (Fig 2, lane 5). Scatchard plot analysis showed that approximately 60% reduction of AT1-R number by 200 µmol/L SNAP (Bmax: 2.6 fmol/well versus 6.7 fmol/well in control) without changing the dissociation constant of Sarile to VSMC (Table 1). Bmax in SNAP-stimulated and control VSMC corresponds approximately to 43.4 fmol/mg protein and 111.9 fmol/mg protein, respectively. The saturation curve and scatchard plot analysis are shown in Fig 3.
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Effect of SNAP on mRNA Stability
To determine whether SNAP has an effect on mRNA stability, mRNA stability was examined by using actinomycin D, which is an inhibitor of gene transcription. After 3 hours of stimulation with SNAP, actinomycin D was added to VSMC, and AT1-R mRNA was examined in the time indicated in Fig 4. As shown in Fig 4, SNAP did not affect the breakdown of AT1-R mRNA. Two-way ANOVA showed that there is no statistical difference in the time-dependent decrease of AT1-R mRNA by actinomycin D between control group and SNAP-treated group.
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cGMP Analogue Did Not Affect the Expression Level of AT1-R mRNA in VSMC
Activation of guanylyl cyclase is one of the important signaling mechanism of NO.2,3 To determine whether SNAP-induced downregulation of AT1-R mRNA is mediated by cGMP-dependent pathway, VSMC were stimulated with a membrane-permeable cGMP analogue, 8 Bromo cGMP (8Br-cGMP). As shown in Fig 5, 8Br-cGMP slightly increased the expression level of AT1-R mRNA. However, the increase was not statistically significant. This suggests that SNAP-induced downregulation of AT1-R mRNA is independent of cGMP.
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Proximal Promoter Region Is Important for SNAP-Induced AT1-R Downregulation
To clarify the molecular mechanism for SNAP-induced AT1-R downregulation, deletion mutants of the promoter region of rat AT1a gene were prepared and fused to luciferase reporter gene as shown in Fig 6A. These AT1-R promoter-luciferase fusion DNA constructs were introduced to VSMC. After 48 hours of transfection, SNAP (200 µmol/L) was added, and the VSMC were cultured for additional 24 hours. Luciferase activity of each construct, which is normalized by ß-galactosidase activity obtained by contransfected pSV2LacZ, is shown in Fig 6B. Successive deletion of the promoter region showed significant decrease of normalized luciferase activity. The suppressive effect of SNAP on the AT1-R gene promoter activity was, however, observed in the shortest deletion mutant (No. 5) that contains 61 bp upstream from transcription start site. Therefore, we assumed that the DNA segment between -61 bp and +25 bp is responsible for the suppression of AT1-R gene promoter activity by NO.
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Suppression of DNA Binding Protein by SNAP
Next we examined DNA binding proteins that bound to the DNA segment between -61 bp and +25 bp. Gel mobility shift assay using nuclear extracts from unstimulated VSMC showed two DNA binding proteins bound to this DNA segment (Fig 7, lane 1, arrows 1 and 2). Specificity of the binding is confirmed by adding 50 times molar excess of nonlabeled probe that eliminates these two bands (lane 2). When nuclear extracts from SNAP-stimulated VSMC were used, one DNA binding protein (arrow 2) could not be observed. Therefore, lack of this DNA binding protein in SNAP-stimulated cells may account for the downregulation of AT1-R gene expression by NO.
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Discussion |
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In this study, we have demonstrated that NO donor down-regulates AT1-R gene expression of VSMC. The effect of NO on the suppression of AT1-R gene expression is independent of cGMP. We have also shown that proximal promoter region of AT1a-R gene and one of two DNA binding protein bound to this proximal promoter region may be responsible for this suppressive effect of NO on AT1-R gene expression.
NO inhibits growth of VSMC.26 It is possible that AT1-R gene is nonspecifically downregulated as general inhibition of VSMC metabolism by NO. However, the inhibitory effect of NO (or NO donor) on the AT1-R-gene expression is not nonspecific because the expression level of actin mRNA was hardly affected by SNAP. NO donor also inhibits Ang II-induced migration of VSMC.27 This effect was mimicked by a membrane-permeable cGMP analogue, 8 Br-cGMP. The inhibitory effect of NO on VSMC growth is also cGMP dependent. Our results showed that the suppressive effect of NO on AT1-R gene expression is independent of cGMP. Therefore, the signaling pathway of antimigratory and growth-inhibitory effect of NO is different from that of downregulation of AT1-R gene expression. Yu et al28 reported that cGMP-elevating agents such as NO donor inhibit ras-dependent activation of raf-1 in epidermal growth factor-stimulated VSMC. Other pathways that may be independent of raf-1 may play a role in the downregulation of AT1-R gene expression. However, the precise signaling mechanism of NO other than activation of guanylyl cyclase is still unclear.
We showed that mRNA stability of AT1-R was not affected by NO. And NO suppressed luciferase activity of luciferase gene driven by heterologous AT1-R gene promoter. These results suggest that the effect of NO on AT1-R gene expression occurs at the transcriptional level rather than by posttranscriptional modification.
NO downregulates AT1-R number in VSMC without a significant change of the affinity of Ang II to AT1-R. Although the estimated AT1-R number in VSMC (Bmax) is in good agreement with previous reports,29,30 the affinity (Kd) was lower than that of previous reports. This may be due to our using whole cell for the Ang II binding assay rather than membrane preparation. Although the affinity of [125I] Sarile to our VSMC is weaker than that of previous reports, it is clear from our results that SNAP does not change the affinity of Ang II to AT1-R. SNAP also suppressed AT1-R mRNA expression in VSMC derived from Wistar Kyoto rats (WKY), but the expression level of AT1-R mRNA is lower than that from SHR (data not shown). Therefore, the results shown in this study are not limited to VSMC from SHR. However, we have not tested VSMC other than those from SHR and WKY.
When endothelium is injured or exposed to hypercholesterolemia,31 NOS activity is decreased. Our results suggest that AT1-R may be upregulated and contribute to proliferation of VSMC and matrix production induced by Ang II when NOS activity is decreased. These may lead to restenosis of injured artery or progression of atherosclerosis. The sequences described above, that is, decrease of NO activity, upregulation of AT1-R, increase of the sensitivity to Ang II, VSMC proliferation and matrix production, progression of atherosclerosis and neointimal formation, and further decrease of NO activity, may form a vicious circle. Nakayama et al32 showed that Ang II attenuated inducible NOS expression by interleukin 1. Signal from increased AT1-R may decrease NO production from inducible NOS by suppressing its expression resulting in the further decrease of NO.
Preliminary results by Cahill et al33 showed that the Ang II receptor number in VSMC is decreased by NO donor. Our results are in good agreement with their results. However, they observed about 10 hours of time lag between stimulation of VSMC by NO donor and the decrease of AT1-R number. In contrast, a NO-induced decrease of AT1-R mRNA occurred as early as 3 hours after stimulation. This may be due to the difference of stability between AT1-R mRNA and AT1-R protein. Although less than 10% of AT1-R mRNA is present in VSMC stimulated with 200 µmol/L of SNAP for 24 hours, about 40% of AT1-R protein remains in VSMC. The differential stability between AT1-R mRNA and protein may also account for this discrepancy. In terms of the luciferase activity, about 50% reduction of luciferase activity by SNAP was observed. The difference between mRNA level of AT1-R and luciferase activity may be ascribed to the same reason. In addition to the result of Cahill et al,33 we have found that the downregulation of AT1-R occurs at mRNA level. Especially, we showed that proximal promoter region is important for the downregulation of AT1-R gene. One of two DNA binding proteins bound to this DNA segment was decreased or lost when VSMC was stimulated with SNAP. However, the possibility that NO modulates the affinity of the DNA binding protein to this DNA segment is not excluded. At present, the precise nature of these DNA binding proteins is not known. However, preliminary results of gel mobility shift assay suggest that these two nuclear proteins bind to the upstream region of the proximal promoter of AT1-R gene, and characterization of these proteins is in progress.
Little is known about the regulation of gene transcription by NO. Pilz et al34 showed that NO activates gene transcription in fibroblasts via the AP-1 consensus element that fos and Jun heterodimeric DNA binding protein binds. This effect is mimicked by 8Br-cGMP, a result suggesting that NO-AP-1 pathway depends on guanylyl cyclase. Therefore, it is unlikely that activation of AP-1 causes NO-induced downregulation of AT1-R gene expression that is independent of cGMP pathway. Tabuchi et al35 reported NO-induced attenuation of AP-1 activity, which is important for neuronal cell death. AP-1 DNA binding activity was dose-dependently suppressed by NO donor. However, fos mRNA level remained constant, suggesting that AP-1 binding activity is posttranscriptionally attenuated by NO. These two contradictory results suggest that NO may elicit different effect on AP-1 DNA binding activity depending on cell type. An AP-1 consensus element is found in the promoter region of AT1a-R gene up to 980 bp upstream from the transcription initiation site (Fig 6A). However, the proximal promoter region of AT1-R gene (-61/ +25) lacks this consensus sequence. Therefore, AP-1 may be irrelevant to NO-induced downregulation of AT1-R gene expression in this DNA segment. NO is also reported to decrease NF-
b-like DNA binding activity that is induced by cytokine stimulation such as interleukin-1 or tumor necrosis factor (TNF) . Inhibition of vascular cell adhesion molecule (VCAM)-1 gene expression in endothelial cells induced by TNF correlated well with the downregulation of NF-b-like DNA binding activity.36 The authors speculated that downregulation NF-b DNA binding activity by NO is responsible for the inhibition of TNF-mediated VCAM-1 gene activation. Although the NF-b-like sequence is also present in the upstream region of AT1a-R gene promoter, there is no NF-b-like sequence in the proximal promoter region.
As seen in the Fig 6B, successive deletion of the promoter region of AT1a-R gene reduced the luciferase activity except for the deletion of the DNA segment between -755 bp and -331 bp that enhanced the luciferase activity. In all these constructs, SNAP also suppressed luciferase activity. Because the difference in the reduction rate of relative luciferase activity by SNAP among these constructs is not statistically significant (Fig 6C), we speculated that the proximal promoter region is important for SNAP-induced downregulation of AT1-R gene expression. However, we have not excluded the possibility that the upstream promoter region also plays a role for the downregulation of AT1-R gene by NO. In particular, the role of AP-1 and NF-B in NO-induced downregulation of AT1 gene will be evaluated in future study.
In this study, we have shown a molecular basis for the downregulation of AT1-R gene expression by NO. In particular, we have found that the proximal promoter region of AT1-R gene is important for the downregulation by NO and that one DNA binding protein is missed when VSMC is stimulated with SNAP. Characterization of this NO-suppressible DNA binding protein and evaluation of the role of cis DNA elements whose activity is modulated by NO in the upstream region of the AT1-R gene promoter will be necessary for further understanding of the mechanism. The results shown here are important not only for the regulatory mechanism of AT1-R gene transcription, but also for the understanding of anti-atherogenic property of NO.
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Acknowledgments |
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This study was supported by grants from the Study Group of Molecular Cardiology, Tokyo, Japan; Kaibara Morikazu Medical Science Promotion Foundation, Fukuoka, Japan; Kimura Memorial Heart Foundation Research Grant for 1996, Kurume, Japan; and Grant-in Aid for Scientific Research from Ministry of Education, Science and Culture, (06404034) Tokyo, Japan.
Received September 16, 1997; first decision October 10, 1997; accepted October 22, 1997.
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