(Circulation. 1999;99:2864-2870.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
T-786
C Mutation in the 5'-Flanking Region of the Endothelial Nitric Oxide Synthase Gene Is Associated With Coronary Spasm
From the Department of Cardiovascular Medicine, Kumamoto University School of Medicine; and the Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine (Y. Saito, Y.O., Y.M., K.N.), Japan.
Correspondence to Hirofumi Yasue, Department of Cardiovascular Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan. E-mail yasue{at}kumamoto-u.ac.jp
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Background—Coronary spasm plays an important role in the pathogenesis of ischemic heart diseases in general. However, the precise mechanism(s) responsible for coronary spasm remains to be elucidated, and we examined the molecular genetics of coronary spasm.
Methods and Results—We searched for the possible mutations in the
endothelial nitric oxide synthase (eNOS) gene in
patients with coronary spasm. In this study, we demonstrate the
existence of 3 linked mutations in the 5'-flanking region of the eNOS
gene (T-786
C, A-922G, and
T-1468A). The incidence of the mutations was
significantly greater in patients with coronary spasm than in
the control group (P<0.0001). Multiple logistic
regression analysis with forward stepwise selection using the
environmental risk factors and the eNOS gene variant revealed that the
most predictive independent risk factor for coronary spasm was
the mutant allele (P<0.0001). As assessed by
luciferase reporter gene assays, the T-786C mutation
resulted in a significant reduction in eNOS gene promoter activity
(P<0.05), whereas neither the A-922G
nor the T-1468A mutation had any affect.
Conclusions—Taken together, these findings strongly suggest that
the T-786C mutation in the eNOS gene reduces the
endothelial NO synthesis and predisposes the patients
with the mutation to coronary spasm.
Key Words: spasm • nitric oxide • genes
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Introduction |
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Coronary spasm plays an important role in the pathogenesis of not only variant angina but also ischemic heart diseases in general, including other forms of angina pectoris, acute myocardial infarction, and sudden death.1 2 3 However, the precise mechanism(s) responsible for coronary spasm remains to be elucidated.
In the endothelium of both animals and humans, synthesis of nitric oxide (NO) from the amino acid L-arginine is catalyzed by the enzyme endothelial NO synthase (eNOS),4 and the continuously generated NO serves to maintain basal vascular tone.5 6 In patients with coronary spasm, the basal tone of the coronary arteries is increased, and they are hyperresponsive to the vasodilator action of nitroglycerin.7 8 9 Nitrovasodilators, including nitroglycerin, reduce vasomotor tone by way of their in vivo conversion to NO,4 10 11 and the hyperreactivity to nitrovasodilators seen in patients with coronary spasm is consistent with decreased endothelial release of NO.4 11
The effects of acetylcholine (ACh) on coronary arterial tone provide further evidence of decreased NO synthesis in patients with coronary spasm. We and others have shown that intracoronary injection of ACh elicits severe vasoconstriction in these patients,12 13 14 whereas ACh causes coronary vasodilatation in subjects with healthy coronary arteries.14 15 16 17 ACh-induced vasodilatation is mediated by NO released from the endothelium.4 18 Therefore, it seems possible that the endothelium in the coronary arteries of patients with coronary spasm is dysfunctional and NO release in response to ACh is decreased. Indeed, we recently showed that basal, ACh-stimulated, and flow-dependent NO activities are decreased in both coronary and brachial arteries of the patients with coronary spasm.8 19 20
The prevalence of coronary spasm appears to be higher in the Japanese population than in whites,21 22 which suggests that genetic factors may be involved in its pathogenesis. We therefore hypothesized that eNOS may play an important role in the pathogenesis of coronary spasm and that there may be possible mutations of the eNOS gene in patients with coronary spasm. In this study, we examined possible mutations in the 5'-flanking region of the eNOS gene that may be associated with coronary spasm.
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Methods |
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Study Patients
To search for possible mutations in the eNOS gene, we performed polymerase chain reaction–single-strand conformation polymorphism (PCR-SSCP) analysis in 11 patients (11 women; mean age, 49 years; range, 33 to 65 years) with coronary spasm and 9 control subjects with atypical chest pain (3 men and 6 women; mean age, 52 years; range, 35 to 70 years). We defined coronary spasm as an abnormal contraction of an epicardial coronary artery resulting in myocardial ischemia2 23 and not by an abnormal constrictor response to ACh. All 11 patients had experienced episodes of spontaneous angina associated with ST-segment changes. In this study, coronary spasm associated with ischemic ST-segment changes was angiographically documented during cardiac catheterization; spasm occurred spontaneously in 2 patients and was induced by intracoronary injection of ACh in the others. In all patients, coronary arteries were normal or almost normal after intracoronary injection of isosorbide dinitrate. All control subjects also underwent coronary angiography for evaluation of chest pain. They exhibited angiographically normal or nearly normal coronary arteries and did not show coronary spasm after intracoronary injection of ACh.
To further determine the extent to which detected mutations were associated with coronary spasm, we examined the incidence of the mutations in a larger test population. This study population included 174 patients with coronary spasm (90 men and 84 women; mean age, 61 years; range, 25 to 78 years) and 161 control subjects (91 men and 70 women; mean age, 59 years; range, 31 to 80 years) who were admitted consecutively at our institution between November 1995 and March 1997. In all of these patients, coronary spasms associated with ST-segment changes were angiographically documented during spontaneous attacks (11 patients) or after intracoronary injection of ACh (163 patients). After intracoronary injection of isosorbide dinitrate, the patient's coronary arteries appeared normal and exhibited no significant organic stenosis (<50% luminal diameter). The control subjects all underwent diagnostic cardiac catheterization, including coronary angiography, for evaluation of chest pain. They had angiographically normal or nearly normal coronary arteries and did not exhibit coronary spasm after intracoronary injection of ACh.
All subjects enrolled in the study gave informed consent. The study protocol was in agreement with the guidelines of the ethics committee at our institution.
PCR-SSCP Analysis and Direct Sequencing
Genomic DNA was prepared from blood leukocytes. PCR-SSCP
analysis was carried out as reported previously.24
Briefly, on the basis of its known genomic
structure,25 26 27 we divided the 5'-flanking region of the
eNOS gene (nucleotide positions -1533 to +44) into 14
overlapping segments designated F1 to F14 (Figure 1
). The sequences of the primers used in
the PCR-SSCP analysis are shown in Table 1. Heat-denatured PCR products
were separated by electrophoresis on polyacrylamide gels at 3 W
for 16 to 18 hours under 3 gel conditions: 5% and 10% glycerol at
4°C and 5% glycerol at room temperature. The PCR products were
then directly sequenced with an automated sequencer (ABI 373S, USA),
and all DNA sequences were confirmed by reading of both DNA
strands.
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Allele-Specific Oligonucleotide Method
The allele-specific oligonucleotide method
was used to examine the frequency at which
T-786C, A-922G, or
T-1468A mutations appeared in the larger test
population. The F7, F9, and F14 fragments were each amplified by PCR
under the same conditions as were used for PCR-SSCP analysis.
Each PCR product was blotted in duplicate onto nylon membranes.
Hybridization was then done with 32P-radiolabeled
oligonucleotide probes corresponding to either the
normal gene sequence (5'-GGGTCAGCCAGCCAGGGAA-3',
5'-AGTTCTGTGTCATCTGAGG-3', or 5'-GACAACAGAACCCAAGTCT-3'), which
included T-786, A-922,
and T-1468, respectively, or the mutant gene
sequence (5'-GGGTCAGCCGGCCAGGGAA-3', 5'-AGTTCTGTGCCATCTGAGG-3', or
5'-GACAACAGATCCCAAGTC T-3'), which included
C-786, G-922, and
A-1468, respectively.
Construction of eNOS Reporter Vectors
DNA fragments from the 5'-flanking region of the eNOS gene
(nucleotide positions -1600 to +26), with and without the
3 previously described point mutations, were amplified by PCR with the
genomic DNA. Upstream and downstream primers containing KpnI
and XhoI sites, respectively, were synthesized, and the PCR
products were digested and fused into the luciferase reporter gene
vector PGV-B2 (Toyo Inc). The eNOS promoter/luciferase reporter gene
plasmids containing either the normal sequence or all 3 mutations were
designated pPGV-eNOSwt and pPGV-eNOSmt, respectively. To construct eNOS
promoter/luciferase reporter gene plasmids, each with only 1 of the 3
mutations, the BsmI/XhoI DNA fragment (-855 to
+44), BsmI/BsmI DNA fragment (-1333 to -855),
or KpnI/BsmI DNA fragment (-1600 to -1333) were
excised from pPGV-eNOSmt and substituted for the corresponding
fragments in pPGV-eNOSwt. The eNOS promoter/luciferase reporter gene
plasmids, containing either the T-786C,
A-922G, or T-1468A
mutations, were designated pPGV-eNOSmt1, pPGV-eNOSmt2, and
pPGV-eNOSmt3, respectively.
Cell Culture
Human umbilical vein endothelial cells (HUVECs)
were cultured in medium supplemented with 2% FBS at 37°C under an
atmosphere of 5% CO2. Before transfection, the
cells were transferred to 6-well dishes and allowed to grow until they
were 
80% confluent, at which time they were transfected. Cells were
used for up to 3 passages.
Luciferase Reporter Gene Assays
Transient transfections were performed with TransIT-LT2 (Pan
Vera Corp) used according to the manufacturer's instructions. The
promoter/luciferase reporter gene (1.5 µg) was cotransfected with 1
µg ß-actin–driven ß-galactosidase reporter plasmid. After
transfection, promoter activity was evaluated in HUVECs incubated for
48 hours under normoxic conditions. For the hypoxia-stimulation
experiment, transfected HUVECs were exposed to normoxia for 24 hours
and then exposed to hypoxia (1% O2, 5%
CO2, and 94% N2) for an
additional 24 hours. HUVECs were then pelleted, resuspended in reporter
lysis buffer (LCß-PGC; Toyo Inc), and centrifuged to remove
cell debris. The extracts were then used for measurement of luciferase
(20 µL) or ß-galactosidase (10 µL) activities. Luciferase
activity was measured in triplicate with a luminometer (Lumat LB 9507;
Prof Dr Berthold, GmbH), and ß-galactosidase activity was measured
spectrophotometrically (at 410 nm). All data were normalized as
relative light units/ß-galactosidase activity.
Statistical Analysis
When the clinical characteristics of the study patients were
considered, hypertension was operationally defined as blood pressures
>140/95 mm Hg, and diabetes mellitus was defined as fasting
blood glucose levels >140 mg/dL or >200 mg/dL in an oral glucose
tolerance test.
Continuous variables were compared by 2-tailed unpaired
t tests. Categorical variables were compared by
2 analysis with Fisher's exact
probability. Odds ratios (approximating relative risk) were calculated
as an index of the association of the eNOS genotype (normal
homozygote, heterozygote, abnormal homozygote) with the
phenotype of coronary spasm. For each odds ratio, we
calculated 2-tailed probability value and 95% CIs. The effects of the
mutant allele were assumed to be either additive, dominant, or
recessive; values for the additive effect were predicted by the
Hardy-Weinberg equilibrium.
Multiple logistic regression analysis with forward stepwise
selection (Wald) was performed with SPSS Advanced Statistics 6.1 for
the Macintosh (SPSS Japan Inc). Independent variables were coded as
the following dummy variables: genotype, 0 for normal
homozygotes and 1 for abnormal homozygotes or heterozygotes; sex, 0 for
female and 1 for male; age, 0 for <60 years and 1 for 
60 years; body
mass index, 0 for <26 kg/m2 and 1 for 26
kg/m2;
hypercholesterolemia, 0 for <240 mg/dL and 1
for 240 mg/dL; cigarette smoking, 0 for nonsmokers and 1 for smokers;
hypertension, 0 for normotension and 1 for hypertension; and diabetes
mellitus, 0 for absence and 1 for presence.
Promoter activities were assessed as a function of normalized luciferase activities in pairs of experiments and were compared by 2-tailed unpaired t tests.
Statistical significance was defined as P<0.05.
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Results |
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Detection and Identification of Mutations and Sequencing of the 5'-Flanking Region of the eNOS Gene
To identify possible mutations in the 5'-flanking region of the eNOS gene, we performed PCR-SSCP analysis on genomic DNA extracts from 11 typical patients with coronary spasm and 9 control subjects. In 4 of the 11 patients with coronary spasm, we discovered the presence of variant bands in PCR products of the F7, F9, and F14 fragments, but no variant bands were seen in the 9 control subjects (Figure 2
). We
subsequently sequenced both the substituted and unsubstituted fragments
(Figure 3) and identified 3 point
mutations: a T-to-C mutation at nucleotide position -786,
an A-to-G mutation at nucleotide position -922, and a
T-to-A mutation at nucleotide position -1468. These
results were confirmed by complete sequencing of the eNOS gene from
nucleotide position -1533 to +44. The sequence of the gene
from subjects with variant bands (mutant-type) was virtually identical
to that of the control subjects except for the 3 substitutions
described above. Nucleotide positions are expressed
relative to the previously described transcriptional initiation
site.26
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Association of eNOS Gene Mutation With Coronary Spasm
Each point mutation was examined in 174 patients and 161 control
subjects by the allele-specific oligonucleotide
method. This analysis revealed that the 3 mutations were always
linked with each other (100% concordance); thus, the allele
frequency was identical among the 3 mutations. The eNOS
allele/T-786C,
A-922G, and T-1468A
homozygotes, heterozygotes, and normal homozygotes were present in
3 (2%), 48 (28%), and 123 (70%) of the 174 patients with
coronary spasm, respectively. Conversely, the abnormal
homozygotes, heterozygotes, and normal homozygotes were found in none
(0%), 11 (7%), and 150 (93%) of the 161 control subjects,
respectively. The frequencies of the genotypes were in
agreement with those predicted by the Hardy-Weinberg equilibrium
(P>0.05). When the additive and dominant effect of the
mutant eNOS allele was analyzed, the incidence of the
abnormal allele was significantly higher in the coronary
spasm group than in the control group (P<0.0001; Table 2).
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Clinical Characteristics of the Study Patients and Multiple
Logistic Regression Analysis
The incidences of coronary risk factors, including age,
sex, total cholesterol, hypertension, diabetes mellitus,
body mass index, and cigarette smoking, were compared in the control
and coronary spasm groups. The incidence of cigarette smoking
was significantly higher in the coronary spasm group than in
the control group (P=0.0009), but there were no significant
differences among the other risk factors for the 2 groups (Table 3). We then performed multiple logistic
regression analysis with forward stepwise selection using all
the clinical risk factors and the mutant allele of the eNOS gene.
This analysis revealed that the most predictive independent
risk factor for coronary spasm was the mutant allele
(P<0.0001), followed by cigarette smoking
(P=0.0093; Table 4).
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Promoter Activities of the eNOS Gene
Luciferase reporter gene assays using the 5'-flanking region of
the eNOS gene containing the 3 mutations showed a significant decrease
(-22±6%) in transcriptional activity compared with those that did
not contain the mutations. To determine which mutation was responsible
for the reduction in promoter activity, fragments of the 5'-flanking
regions of the mutant eNOS, each containing only 1 of the 3 point
mutations, were fused with the luciferase reporter gene. As shown in
Figure 4, the
T-786C mutation reduced the promoter activity
significantly (-52±11%) in comparison with the normal sequence,
whereas neither the A-922G nor the
T-1468A mutation reduced promoter
activity.
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When transfected HUVECs were exposed to hypoxia for 24 hours, promoter activity was markedly augmented in all transfected cell groups regardless of the construct (pPGV-eNOSwt, +110±32%; pPGV-eNOSmt, +38±11%; pPGV-eNOSmt1, +69±26%; pPGV-eNOSmt2, +102±26%; and pPGV-eNOSmt3, +92±58%). Moreover, pPGV-eNOSmt and pPGV-eNOSmt1 both exhibited substantial reductions (-50±4% and -62±11%, respectively) in transcriptional activity compared with pPGV-eNOSwt.
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Discussion |
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During the initial screening of this study, we discovered 3 mutations (T-786
C,
A-922G, and
T-1468A) in the 5'-flanking region of the
eNOS gene in the patients with coronary spasm. To further
examine the relationship between these mutations and coronary
spasm, we searched for the mutations in 174 patients with
coronary spasm and 161 control subjects. We found that the
mutations were always linked with each other and that they occurred
more frequently in coronary spasm patients than in the control
group. The distribution of the mutant allele was compatible with
the Hardy-Weinberg equilibrium, indicating that the screening method
was appropriate. Multiple logistic regression analysis of the
mutant allele of the eNOS gene and other coronary risk
factors revealed that the independent risk factor that best predicted
the incidence of coronary spasm was the mutant allele of
the eNOS gene.
To examine the extent to which each of the 3 point mutations modified
eNOS gene expression, we performed luciferase reporter gene assays.
This analysis revealed that only the
T-786C mutation suppressed eNOS gene
transcription. We also showed that hypoxia increased eNOS
promoter activity, which is in agreement with previous
findings.28 The decrease in eNOS transcription is
consistent with the notion that endothelial NO
production is reduced in patients carrying the
T-786C mutation. Thus, the present
results strongly suggest that the presence of the eNOS gene mutant
allele reduces endothelial production of NO
in the coronary arteries and predisposes the patients carrying
the mutant allele to coronary spasm. NO is also known to
suppress production of the potent vasoconstrictors endothelin
and angiotensin II, which also induce vascular smooth
muscle cell proliferation.29 30 Consequently, deficiency
of NO production in vessels in patients with the mutant
allele may also result in increased synthesis of these
vasoconstrictors and in smooth muscle cell proliferation, thereby
leading to increased vessel reactivity. However, controversy still
exists as to whether or not endothelial NO is deficient
in patients with coronary spasm,31 and further
studies are needed. There may be differences in the clinical
characteristics of patients who are homozygous for the mutant eNOS
allele and those who are heterozygous. We found 3 homozygous
subjects among the 335 participants in this association study. These 3
patients suffered from severe coronary spasm, and 2 of the
patients had also experienced acute myocardial infarction without
organic stenosis. It is possible, therefore, that
coronary spasm may be more severe and prolonged in homozygous
subjects than in those who are heterozygous.
In 11 (7%) of the 161 control subjects carrying mutant eNOS alleles, coronary spasm could not be induced by intracoronary injection of ACh in those individuals, although vasoconstrictor responses to ACh were increased. Six of the subjects were smokers, and the histories of all 11 subjects indicated that they had experienced coronary spasm at some time. Because there is daily, monthly, and yearly as well as diurnal variation in the occurrence of coronary spasm,2 3 32 it is possible that these patients were not in the active phase of the ailment at the time of study. It is also possible that they may be destined to suffer from coronary spasm in the future, because they are relatively young (mean age, 50 years; range, 31 to 62 years).
We and others have shown that smoking impairs
endothelium-dependent coronary
arterial dilatation in humans33 34 35 and that
smoking is a major risk factor for coronary
spasm.33 36 We obtained the same result in this study.
Thus, both genetic and environmental factors are involved in the
pathogenesis of coronary spasm. We also performed the
association study in both the smoking and nonsmoking groups. Our
preliminary analysis revealed that the
T-786C mutation is significantly associated
with coronary spasm in each group (odds ratio of additive
effect, 3.79 in the smoking group and 3.05 in the nonsmoking
group).
In our recent study, we found a missense Glu298Asp variant in the eNOS
gene and found that the variant was associated with coronary
spasm.37 In the analyses of the frequencies of the
T-786C and Glu298Asp variants in >1000 DNA
samples, there was no relationship in the linkage between the 2 eNOS
variants. Recently, Wang et al38 reported that the
smoking-dependent risk of ischemic heart disease is associated
with a polymorphism in intron 4 of the eNOS gene. The relationship
between the 3 mutations in the 5'-flanking region that we observed and
the polymorphism in intron 4 of the eNOS gene remains to be
elucidated. Thus, further analyses will be necessary to examine
the other genetic risk factors for coronary spasm.
In conclusion, the present study demonstrates that 3 distinct point
mutations occur in the 5'-flanking region of the eNOS gene
(T-786C, A-922G,
and T-1468A) and that these mutations are
strongly associated with coronary spasm. Furthermore, we
demonstrated that the T-786C mutation
substantially reduces promoter activity of the eNOS gene. Taken
together, these findings strongly suggest that the
T-786C mutation in the eNOS gene compromises
endothelial NO synthesis and predisposes the patients
with the mutant allele to coronary spasm.
Received January 22, 1999; revision received February 23, 1999; accepted March 17, 1999.
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P. M. Spooner, C. Albert, E. J. Benjamin, R. Boineau, R. C. Elston, A. L. George Jr, X. Jouven, L. H. Kuller, J. W. MacCluer, E. Marban, et al. Sudden Cardiac Death, Genes, and Arrhythmogenesis : Consideration of New Population and Mechanistic Approaches From a National Heart, Lung, and Blood Institute Workshop, Part II Circulation, May 22, 2001; 103(20): 2447 - 2452. [Abstract] [Full Text] [PDF]
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K. Okumura, T. Osanai, T. Kosugi, H. Hanada, H. Ishizaka, T. Fukushi, T. Kamada, T. Miura, T. Hatayama, T. Nakano, et al. Enhanced phospholipase C activity in the cultured skin fibroblast obtained from patients with coronary spastic angina: possible role for enhanced vasoconstrictor response J. Am. Coll. Cardiol., November 15, 2000; 36(6): 1847 - 1852. [Abstract] [Full Text] [PDF]
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Y. Miyamoto, Y. Saito, M. Nakayama, Y. Shimasaki, T. Yoshimura, M. Yoshimura, M. Harada, N. Kajiyama, I. Kishimoto, K. Kuwahara, et al. Replication protein A1 reduces transcription of the endothelial nitric oxide synthase gene containing a -786T->C mutation associated with coronary spastic angina Hum. Mol. Genet., November 1, 2000; 9(18): 2629 - 2637. [Abstract] [Full Text] [PDF]
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 G. Gaeta, M. De Michele, S. Cuomo, P. Guarini, M. C. Foglia, M. G. Bond, and M. Trevisan Arterial Abnormalities in the Offspring of Patients with Premature Myocardial Infarction N. Engl. J. Med., September 21, 2000; 343(12): 840 - 846. [Abstract] [Full Text] [PDF]
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Y. Miyao, K. Kugiyama, H. Kawano, T. Motoyama, H. Ogawa, M. Yoshimura, T. Sakamoto, and H. Yasue Diffuse intimal thickening of coronary arteries in patients with coronary spastic angina J. Am. Coll. Cardiol., August 1, 2000; 36(2): 432 - 437. [Abstract] [Full Text] [PDF]
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A. Elbaz, O. Poirier, T. Moulin, F. Chedru, F. Cambien, and P. Amarenco Association Between the Glu298Asp Polymorphism in the Endothelial Constitutive Nitric Oxide Synthase Gene and Brain Infarction Stroke, July 1, 2000; 31(7): 1634 - 1639. [Abstract] [Full Text] [PDF]
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O. Hirashima, H. Kawano, T. Motoyama, N. Hirai, M. Ohgushi, K. Kugiyama, H. Ogawa, and H. Yasue Improvement of endothelial function and insulin sensitivity with vitamin C in patients with coronary spastic angina: Possible role of reactive oxygen species J. Am. Coll. Cardiol., June 1, 2000; 35(7): 1860 - 1866. [Abstract] [Full Text] [PDF]
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R. Busse and I. Fleming A critical look at cardiovascular translational research Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1655 - H1660. [Full Text] [PDF]
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T. F. Luscher and G. Noll Is It All in the Genes... ? : Nitric Oxide Synthase and Coronary Vasospasm Circulation, June 8, 1999; 99(22): 2855 - 2857. [Full Text] [PDF]
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S. Nasreen, T. Nabika, H. Shibata, H. Moriyama, K. Yamashita, J. Masuda, and S. Kobayashi T-786C Polymorphism in Endothelial NO Synthase Gene Affects Cerebral Circulation in Smokers: Possible Gene-Environmental Interaction Arterioscler. Thromb. Vasc. Biol., April 1, 2002; 22(4): 605 - 610. [Abstract] [Full Text] [PDF]
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T. Nakano, T. Osanai, H. Tomita, M. Sekimata, Y. Homma, and K. Okumura Enhanced Activity of Variant Phospholipase C-{delta}1 Protein (R257H) Detected in Patients With Coronary Artery Spasm Circulation, April 30, 2002; 105(17): 2024 - 2029. [Abstract] [Full Text] [PDF]
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