Published online before print July 19, 2004,
doi:10.1161/01.CIR.0000136808.72912.D9
(Circulation. 2004;110:438-443.)
© 2004 American Heart Association, Inc.
Urinary 20-Hydroxyeicosatetraenoic Acid Is Associated With
Endothelial Dysfunction in Humans
Natalie C. Ward, PhD; Jennifer Rivera,
BSc(Hon); Jonathan Hodgson, PhD; Ian B. Puddey, MD; Lawrie J.
Beilin, MD; John R. Falck, PhD; Kevin D. Croft, PhD
From the School of
Medicine and Pharmacology (N.C.W., J.R., J.H., I.B.P., L.J.B.,
K.D.C.), University of Western Australia & West Australian
Institute of Medical Research, Perth, Australia, and Biochemistry
Department (J.R.F.), University of Texas Southwestern Medical
Center, Dallas, Tex.
Correspondence to
Associate Professor Kevin D Croft, School of Medicine &
Pharmacology, Box X2213 GPO, Perth, West Australia 6847. E-mail kcroft@cyllene.uwa.edu.au
Received December 2,
2003; de novo received March 9, 2004; accepted March 30, 2004.
 |
Abstract |
Background— 20-Hydroxyeicosatetraenoic acid
(20-HETE) is a cytochrome P450 (
-hydroxylase) metabolite of
arachidonic acid with vasoconstrictor activity that
may be involved in the pathogenesis of hypertension.
In humans, there are few data relating 20-HETE to
vascular pathophysiology. This study aimed to
determine whether urinary 20-HETE excretion is related to blood
pressure or vascular endothelial function in humans.
Methods and
Results— Sixty-six subjects (37 males, 29 females),
including 29 with untreated hypertension, had urinary 20-HETE
excretion measured by gas chromatography/mass spectrometry. There
was no significant difference for 20-HETE excretion between hypertensive
and normotensive subjects. 20-HETE excretion was positively
related to body mass index and sodium excretion. There
was a significant inverse association between urinary 20-HETE
and endothelium-dependent vasodilation measured by flow-mediated
dilation of the brachial artery (P=0.006). There was
no association with vasodilator responses to
nitroglycerin. In multiple regression analysis,
20-HETE remained an independent predictor of
endothelium-dependent vasodilation after adjustment
for age, body mass index, and blood pressure. When
gender was included in the model, the relationship between
20-HETE and flow-mediated dilation was attenuated. Separate analysis
by gender revealed that in women, hypertensive subjects had
significantly higher 20-HETE excretion than normotensive subjects,
but this was not seen in men. In women, 20-HETE was positively
related to diastolic and systolic blood pressure. In
men, 20-HETE was positively related to body mass index.
Conclusions—
This is the first demonstration of an association between
20-HETE excretion and in vivo vascular function in humans. Given
the negative modulatory role of nitric oxide on -hydroxylase, the
present results suggest a potentially important role for 20-HETE
in human vascular physiology.
Key Words: fatty acids • blood pressure
• hypertension • endothelium
|
Introduction |
Arachidonic acid can be metabolized by cytochrome P-450 (CYP450,
or CYP) enzymes to a range of compounds. These compounds
are thought to play a central role in the regulation
of vascular tone, renal function, and blood pressure
(BP).1,2
In the vasculature, smooth muscle cells produce
20-hydroxyeicosatetraenoic acid (20-HETE) as a major
product of CYP450 metabolism.3
20-HETE causes vasoconstriction by inhibition of
potassium (K+) channels and may serve as an
endogenous intracellular regulator of the K+
channel in arteriolar smooth muscle cells.4
20-HETE may act as a second messenger mediating the
vascular actions of hormones such as endothelin-1 and
angiotensin II.5–7
There is evidence that nitric oxide (NO) inhibits the
formation of 20-HETE by binding to the catalytic heme
site in the CYP450 4A enzyme.8
Indeed, the fall in 20-HETE levels may contribute to the
cGMP-independent activation of K+ channels
and vasodilator response to NO.9
Flow-mediated
vasodilation (FMD) is a physiological mechanism for
regulating blood flow and is largely mediated by NO. This endothelium-dependent
vasodilation may be impaired (endothelial dysfunction)
in cases of vascular disease associated with hypertension or
atherosclerosis, possibly owing to reduced bioavailability of
NO.10,11
Noninvasive high-resolution ultrasound techniques have
been used to measure brachial artery FMD, which reflects endothelium-dependent
vasodilation12
and is a possible surrogate for function of the
coronary circulation.13,14
On the other hand, in the microcirculation,
CYP-derived hyperpolarizing factors may play a greater
role than NO in flow-induced endothelium-dependent vasodilation.15
For example, in coronary arterioles from healthy subjects,
CYP-dependent factors account for most flow-induced dilatation,
with NO playing a minor role.16
Abnormalities in the
production or actions of 20-HETE may be involved in
the pathogenesis of hypertension. There is convincing evidence
in the spontaneously hypertensive rat that increased CYP
expression or 20-HETE synthesis is involved in vasoconstriction
and impaired renal salt handling.2,17–20
In mice, genetic alteration of CYP450 4A monooxygenase
can cause hypertension.21
Little information is available on the involvement of
20-HETE in human hypertension. Recently, Laffer et al22
demonstrated differential regulation of natriuresis by
20-HETE in human salt-sensitive hypertension compared
with salt-resistant hypertension; however, there was
no difference in 20-HETE excretion between the 2 groups of
hypertensive subjects.
One reason for the
lack of information linking 20-HETE production to
human pathophysiology is the difficulty in measuring endogenous
20-HETE in biological fluids. 20-HETE is excreted in the
urine as the glucuronide and can be measured by
sensitive and specific gas chromatography mass
spectrometric methods after hydrolysis with
glucuronidase.23
We were particularly interested in examining potential
links between formation of the CYP-derived vasoconstrictor, 20-HETE,
and cardiovascular physiology. In the present study, we
assessed urinary 20-HETE excretion in a group of healthy normotensive
subjects and subjects with untreated hypertension. Although
20-HETE excretion did not differ significantly between normotensive
and hypertensive subjects, we observed highly significant associations
between 20-HETE excretion, body mass index (BMI), and
endothelial function.
|
Methods |
Study Protocol
Thirty-seven normotensive subjects (with a mean 24-hour
ambulatory systolic BP 
125 mm Hg and a mean daytime ambulatory
systolic BP 130 mm Hg)
and 29 hypertensive subjects (with a mean 24-hour ambulatory
systolic BP 
135 mm Hg or a mean
daytime ambulatory systolic BP 140 mm Hg) who had never been treated for
hypertension were recruited from the Perth general
population to the School of Medicine and Pharmacology
of the University of Western Australia. The study was
approved by the Royal Perth Hospital Human Ethics Committee,
and written informed consent was provided before inclusion
in the study.
All volunteers were
otherwise healthy and ceased any vitamin, antioxidant,
or fish oil supplements for a minimum of 4 weeks before
study entry. Exclusion criteria included hyperlipidemia, use
of lipid-lowering therapy, previous coronary or cerebrovascular
event, heart failure, premenopausal status in women, use of
oral contraception, use of nitrate medication, smoking, or
BMI >35 kg/m2. All volunteers had their
height and weight measured, underwent fasting brachial
ultrasonography to assess responses to ischemic FMD
and nitroglycerin (NTG)-mediated dilation, were fitted
with a 24-hour ambulatory BP monitor, and provided a 24-hour
urine collection and a fasting blood sample. Urine and plasma
samples were stored at –80°C.
24-Hour
Ambulatory BP Monitoring
Twenty-four-hour BP monitoring was performed with an ambulatory
BP-monitoring device (Spacelabs 90207), set to take
oscillometric readings at 20-minute intervals while
the subject was awake and 30-minute intervals while
the subject was asleep. The monitor was fitted to the
nondominant arm 
2.5
cm above the antecubital fossa by a trained
researcher. Patients rested their arms at heart level,
and BP was calibrated against a mercury sphygmomanometer. Patients
were instructed to continue their normal routine and maintain
a diary throughout their awake hours. A valid 24-hour recording
was accepted as a minimum of 80% successful readings with
all readings taken during the calibration and any error readings
excluded from analysis. Readings were aggregated for each
hour, and mean BP was determined for the 24-hour period and
for awake and asleep times based on the patient’s diary.
Brachial
Artery Ultrasonography
Brachial artery ultrasonography was performed as described
previously.24
Briefly, patients were studied after a 12-hour fast and
after resting supine in a quiet,
temperature-controlled room (21°C to 25°C). A 12-MHz
transducer connected to an Acuson Aspen 128 ultrasound
(Acuson Corporation) was used, together with continuous
ECG monitoring. The ultrasound probe was placed 5 to
10 cm proximal to the antecubital crease on the left arm and
held in position on the brachial artery by a clamp. Images were
recorded on Super VHS videotape (Sony MQSE 180) for retrospective
analysis. A BP cuff was placed around the upper right arm,
and an inflatable cuff was placed around the left
forearm. After 1 minute of scanning to record the
baseline artery diameter, the forearm cuff was rapidly
inflated to 200 mm Hg or 50 mm Hg above systolic BP
for 5 minutes. Reactive hyperemia was induced by
release of the cuff, and scanning was recorded for an additional
4 minutes to assess FMD. Doppler flow velocity and flow
rate (mL/min) were calculated during baseline and the
first 15 seconds of reactive hyperemia. A second
resting baseline scan was obtained at least 10 minutes
after cuff deflation. NTG (400 µg) was sprayed
sublingually and the artery scanned again for 6 minutes
to assess NTG-mediated dilatation. Analysis of FMD and NTG
response of the brachial artery was performed with semiautomated
edge-detection software.24
The computerized edge-detection and wall-tracking
software automatically calculated brachial artery diameter,
which corresponded to the internal diameter and was gated
to the R wave of the ECG, with measurements taken at end diastole.
An experienced observer blinded to the patient’s status
performed the analysis. Responses were calculated as the
percentage change in brachial artery diameter from baseline at
maximum peak time. Reproducibility studies have previously demonstrated
an intrasubject coefficient of variation of 14.7% and
17.6% for FMD and NTG response, respectively,24
which is comparable to that observed in other studies.25
Analysis of
20-HETE
Analysis of 20-HETE was performed with stable isotope dilution
gas chromatography/mass spectrometry as previously
described in detail.26
Briefly, deuterated 20-HETE (2 ng, internal standard) was
added to 2 mL of freshly thawed urine. After incubation with
Escherichia coli ß-glucuronidase (0.2 mg, 2 hours at
37°C), the sample was diluted with 2 mL of 0.1 mol/L sodium
acetate buffer containing 5% methanol, and the pH was adjusted
with 10% acetic acid to pH 6. 20-HETE was extracted with
a Bond Elut-Certify II column (Varian) and further purified by
high-performance liquid chromatography. The pentafluorobenzyl
ester and tert-butyldimethylsilyl derivatives were prepared
and analysis by negative chemical ionization gas
chromatography/mass spectrometry, monitoring ions m/z
433 and m/z 435 (internal standard).
Biochemistry
Twenty-four hour urinary sodium was analyzed with an
ion-selective electrode unit and serum and urinary
creatinine with a standard kinetic colorimetric assay
in the Department of Clinical Biochemistry at Royal
Perth Hospital. Fasting plasma and 24-hour urine were analyzed
for total NO production (nitrate plus nitrite) with a
colorimetric assay kit (Cayman).
Statistical
Analysis
Statistical analysis was performed with the Statistical Package
for the Social Sciences (SPSS version 11.5). Nonnormally
distributed data were log-transformed. Results are
presented as mean±SEM or geometric mean (95% CIs) for
nonparametric data. Independent-sample t tests
were used to determine differences between the 2 groups. Univariate
ANOVA was used to determine differences. The relationship between
FMD response and 20-HETE levels was determined before and
after adjustment for age, BMI, and mean 24-hour systolic BP.
|
Results |
Subject Characteristics
Subjects had a mean age in the mid-50s, and men predominated
in the untreated hypertensive group (Table
1). Mean 24-hour ambulatory systolic and diastolic
BPs were significantly different between the 2 groups
(P<0.001). All hypertensive subjects had BPs
greater than the threshold guidelines suggested for the
definition of hypertension using 24-hour ambulatory BP
monitoring.27
There was no significant difference between the 2 groups
for age, BMI, urinary sodium excretion, creatinine
clearance, or total plasma or urinary NO production.
Urinary
20-HETE and Correlations With Clinical Variables and Vascular
Function
There was no significant difference between hypertensive subjects
and normotensive controls for 20-HETE excretion expressed
either in concentration (pmol/L) or per 24-hour period
(pmol/24 h; Table
1). In the whole group, there was no significant relationship
between urinary 20-HETE excretion (pmol/24 h) and
ambulatory BP. There was a significant positive
relationship between 20-HETE excretion and BMI (r=0.419,
P<0.0001; Figure
1). Urinary sodium excretion appeared to be
positively related to 20-HETE (pmol/24 h; b=0.99);
however, this did not reach statistical significance (P=0.08;
Table
2).
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Figure
1. Correlation of BMI (kg/m2) with
urinary 20-HETE excretion in all subjects (n=66).
Spearman correlation coefficient r=0.419 (P<0.0001).
|
|
There was no
significant difference for baseline brachial artery diameter
between the hypertensive subjects and controls. There was
a significant negative relationship between 20-HETE excretion
rate (pmol/24 h) and FMD response (r=–0.331, P=0.007;
Figure
2). There was no significant relationship between urinary
20-HETE and NTG response (Table
2). Subjects with an FMD response <5% had
significantly greater 20-HETE excretion than those with
FMD response >5% (P<0.001; Figure
3). There was a significant positive relationship
between 20-HETE (pmol/24 h) and artery diameter (Table
2). A scatterplot of this relationship is
illustrated in Figure
4. Removal of the participant with a brachial
artery diameter of 0.9 mm did not alter the significance of
this relationship (P<0.01).
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Figure
2. Correlation of percent change in FMD of
brachial artery with urinary 20-HETE excretion in
all subjects (n=66). Spearman correlation
coefficient r=–0.331 (P=0.007).
|
|
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Figure
3. Urinary excretion of 20-HETE in all
subjects with FMD response of either <5% (n
=22) or >5% (n =43) irrespective of BP.
Results are expressed as geometric mean (95%
CIs). *Significant difference in 20-HETE
excretion, P=0.001. |
|
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Figure
4. Correlation of brachial artery diameter
with urinary 20-HETE excretion in all subjects
(n=66). Spearman correlation coefficient r=0.328
(P=0.008). |
|
In multiple
regression analysis, after adjustment for age, BMI, and
mean 24-hour systolic BP, 20-HETE (pmol/24 h) remained an independent
predictor of FMD response (P=0.01). However, the further
addition of gender to the model resulted in a loss of statistical
significance (P=0.065).
Subjects were then
analyzed separately by gender. Overall, men had
significantly higher levels of 20-HETE than women (mean [95%
CI] 528 [413–675] versus 338 [279–409] pmol/24 h;
P=0.007). In men, there was no significant difference in
20-HETE excretion between untreated hypertensive subjects
and controls. However, in women, untreated
hypertensive subjects had higher 20-HETE excretion
than normotensive controls (448 [280–716] versus
298 [247–360] pmol/24 h; P=0.041). In men,
there was no significant relationship between 20-HETE excretion
and systolic or diastolic BP (Table
3). BMI was positively associated with 20-HETE
excretion (P=0.002; Table
3) in men. In women, both 24-hour diastolic BP (P=0.005)
and systolic BP (P=0.025) were positively
associated with 20-HETE excretion (Table
3). FMD response was negatively associated with 20-HETE excretion
in women and men, but this trend was not statistically significant
(Table
3).
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TABLE
3. Univariate Relationships With 20-HETE (pmol/24
h) as the Dependent Variable, Within Each Gender,
Analyzed by Linear Regression |
|
|
Discussion |
This study is the first demonstration of a significant
association between 20-HETE excretion and endothelial
function as assessed by FMD of the brachial artery in
humans. There was, however, no difference in the
excretion of 20-HETE between untreated hypertensive
subjects and normotensive subjects. 24-Hour excretion of
20-HETE was not related to BP in the whole group but was positively
associated with BMI. A particular strength of the present
study was that all hypertensive subjects were untreated, which
avoided any possible confounding effects of antihypertensive
therapy.
From extrapolation of
results from animal studies, we had hypothesized that
urinary excretion of 20-HETE would be higher in hypertensive
subjects than in normotensive controls. A recent study
performed in salt-sensitive and salt-resistant
hypertensive subjects observed a positive correlation
between 20-HETE excretion and diastolic BP, but only
in salt-sensitive hypertensive subjects during salt
loading.22
This relationship between 20-HETE and BP was not
observed during the salt-depletion period or in the
salt-resistant hypertensive subjects, which suggests
that 20-HETE excretion is regulated by salt intake
during hypertension.22
In the study by Laffer et al,22
no comparison was made with normotensive subjects, and
20-HETE excretion did not differ between the salt-sensitive and
salt-resistant subjects. In subjects in the present study, there
was a trend for a correlation between sodium excretion and
20-HETE, which supports the suggestion that 20-HETE causes natriuresis.1,27
In the relatively young (53±2 years) untreated
hypertensive subjects in the present study, sodium excretion
and creatinine clearance were not different from that in
normotensive subjects, which may in part explain the lack of
difference in excretion of 20-HETE.
The most striking
finding of the present study was the highly significant
association between 20-HETE excretion and FMD response of
the brachial artery. This remained significant after adjustment
for age, BMI, and mean systolic BP. To the best of our
knowledge, this is the first study to demonstrate this
relationship in humans. 20-HETE excretion was much
higher in subjects with a low FMD response (<5%)
than in those with a normal FMD response, irrespective
of their BP. Because individuals with a large baseline artery
diameter subsequently have a lower FMD response, the positive
relationship between 20-HETE levels and artery diameter may
be influencing the relationship between 20-HETE levels and FMD
response. The relationship between 20-HETE and FMD response must
therefore be interpreted with caution, and it is not unreasonable
to speculate that 20-HETE may be influencing vascular
architecture rather than brachial artery dilation.
However, the positive association between 20-HETE and
brachial artery diameter is perhaps unexpected if it
is assumed that 20-HETE acts as a vasoconstrictor. 20-HETE
is produced in vascular smooth muscle cells and is thought to
play a role in regulating vascular tone.4
The observed association between 20-HETE and FMD
response is consistent with 20-HETE being a
vasoconstrictor that may be upregulated in situations of
low NO bioavailability, as seen in endothelial dysfunction.10,11,28
Although total NO production in the present study was not
different between hypertensive individuals and
controls, and there was no relationship with 20-HETE,
this does not rule out the possibility that 20-HETE
acts as a vasoconstrictor.
Interestingly,
addition of gender to the regression model attenuated the
negative relationship between 20-HETE excretion and FMD response.
Furthermore, when the results were analyzed separately by
gender, different relationships with 20-HETE were observed. Previous
studies in rats have suggested a link between 20-HETE production
and androgens.29
In the present study, we observed overall increased
levels of 20-HETE in men compared with women, which
lends support to the animal model. FMD response, although it
showed the same negative association with 20-HETE in both men
and women, was no longer significant, possibly owing to the
smaller group sizes. In addition, hypertensive women had higher
20-HETE excretion than normotensive women, and within women,
a positive association between 20-HETE and BP was noted. Although
limited by the small number of women, these results do
support the role for sex-dependent mechanisms in the pathogenesis
of hypertension,30
possibly via androgen-mediated regulation of CYP450.29
In future studies, it would be very interesting to
determine 20-HETE excretion in premenopausal women.
It is also intriguing
that we observed a significant positive association
between 20-HETE excretion and BMI. In men, BMI was the
strongest factor associated with 20-HETE excretion. Although
this finding is in contrast to the study by Laffer et al,22
which observed a negative correlation between 20-HETE
excretion and BMI in salt-sensitive hypertensive
subjects (n =13, mean BMI 35.5 kg/m2), the
present study excluded subjects with BMI >35 kg/m2.
Obesity has been linked with insulin resistance31
and increased oxidative stress.32
If increases in reactive oxygen species can reduce NO
bioavailability, then this may be one mechanism for
increased 20-HETE production with increasing BMI. However,
this proposal is not supported by studies in the Dahl salt-sensitive
rat that show that scavenging reactive oxygen species
with Tempol actually increases 20-HETE excretion.33
We know that 20-HETE
is synthesized in the kidney27,34
and excreted in the urine as the glucuronide.23
However, it is uncertain what the contribution of
systemic vascular production of 20-HETE is to the
total urinary 20-HETE concentration. Although much of
the urinary 20-HETE may be of renal origin, it may also reflect
CYP450 metabolism of arachidonic acid to this metabolite at
other vascular sites. These results support the concept for
a role of 20-HETE in vascular function and BP regulation in
humans. An important follow-up to this study would be to
investigate the effects of intervention with agents
such as vitamin C, which may improve endothelial
function, or agents that inhibit CYP450 activity and
determine subsequent changes in 20-HETE excretion. However,
such mechanistic studies are limited by the current lack
of specific CYP450 inhibitors that are suitable for use in
humans.
|
Acknowledgments |
This study was funded by grants from the National Health and
Medical Research Council of Australia (project grant
139067), Centres for Excellence in Clinical Research,
and National Institutes of Health grant GM31278 to Dr
Falck. Natalie Ward acknowledges the assistance of a
University of Western Australia Postgraduate Award.
The authors thank Lisa Rich for performance and analysis of
ultrasounds and the volunteers who took part in the study.
|
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