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28 ReferencesCorrelation between arachidonic acid metabolites and vascular endothelial dysfunction in Chinese elderly with type 2 diabetes mellitus
Abstract
Objective: This study was carried out to determine the correlation between arachidonic acid metabolites and vascular endothelial dysfunction in older Chinese patients diagnosed with type 2 diabetes mellitus. Methods: High-resolution ultrasound was employed to measure flow-mediated dilation (FMD) and sublingual nitroglycerin-induced dilation (NID) of brachial artery. Serum 14,15-dihydroxyeicosatrienoic acid (14,15-DHET), the end-product of 14,15- epoxyeicosatrienoic acid (14,15-EET) and 6-kote-prostaglandin F1 (6-kote-PGF1a), the end-product of prostacyclin (PGI2), were measured in 60 health elderly, 78 senile diabetic patients without nephropathy (SD) and 58 senile diabetic patients with nephropathy (SDN). Results: Compared to healthy elderly, serum 14,15-DHET and 6-kote-PGF1a levels were reduced by 50% in SD. No further decline was observed in SDN. 6-kote-PGF1a was associated with FMD, but not with NID in brachial artery of healthy elderly. FMD and NID in brachial artery were impaired in all diabetic patients. The correlation between FMD and 6-kote-PGF1a or 14,15-DHET was lost in diabetic subjects. On the other hand, NID was positively correlated with 6-kote-PGF1a or 14,15-DHET in SD. Only NID and 6-kote-PGF1a correlation persisted in SDN. In addition, brachial artery dysfunction was negatively correlated with urinary albumin excretion and serum triglyceride in SDN patients. Conclusions: Impaired brachial artery vasodilation was associated with reduced PGI2 and EET production in older Chinese subjects with type 2 diabetes.
8Cardiology Plus 2016, Vol 1. No 2
Correlation between arachidonic acid metabolites and
vascular endothelial dysfunction in Chinese elderly with
type 2 diabetes mellitus
Yali Huang1, Ju Hong Li2, Tong Lu3
1. The Carder’s Ward, No. 411 Hospital of PLA, Shanghai, 200081, P. R. China; 2. Department of Med-
ical examination Center, Shanghai Changhai Hospital, Shanghai, 200433, China. 3. The Department
of Cardiovascular Diseases, Mayo Clinic, Rochester, 55905, USA.
Corresponding author: Tong Lu, M.D., Ph.D., Department of
Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester,
MN55905.
Tel: 507-255-9653; Fax: 507-538-6418; E-mail: lu.tong@mayo.edu.
KEY WORDS: Chinese elderly; type 2 diabetes; diabetic nephropathy; epoxyeicosatrienoic acid; prostacy-
clin; vasodilation
RESEARCH ARTICLES
INTRODUCTION
Diabetes mellitus has become a major public-health crisis in
China with more than 113.9 million people (11.6 % of the total
population) diagnosed and another 493.4 million (50.1% of the
total population) with prediabetes nationwide in 20101. Type
2 diabetes, accounting for between 90~95% of the total cases
of diabetes, is characterized by obesity, glucose intolerance,
insulin resistance, hyperglycemia, dyslipidemia, hyperinsulin-
emia and hypertension. Diabetes is strongly associated with
both microvascular and macrovascular complications, includ-
ABSTRACT
Objective: This study was carried out to determine the correlation between arachidonic acid metabolites
and vascular endothelial dysfunction in older Chinese patients diagnosed with type 2 diabetes mellitus.
Methods: High-resolution ultrasound was employed to measure ow-mediated dilation (FMD) and sub-
lingual nitroglycerin-induced dilation (NID) of the brachial artery. Serum 14,15-dihydroxyeicosatrienoic
acid (14,15-DHET), the end-product of 14,15- epoxyeicosatrienoic acid (14,15-EET) and 6-keto-prosta-
glandin F1α (6-keto-PGF1α), the end-product of prostacyclin (PGI2), were measured in 60 healthy elder-
ly volunteers, 78 senile diabetic patients without nephropathy (SD) and 58 senile diabetic patients with
nephropathy (SDN).
Results: Compared to healthy elderly volunteers, serum 14,15-DHET and 6-keto-PGF1α levels were re-
duced by 50% in SD. No further decline was observed in SDN. 6-keto-PGF1α was associated with FMD,
but not with NID in the brachial artery of healthy elderly volunteers. Brachial FMD and NID were im-
paired in all diabetic patients. The correlation between FMD and 6-keto-PGF1α or 14,15-DHET was lost
in diabetic subjects. On the other hand, NID was positively correlated with 6-keto-PGF1α or 14,15-DHET
in SD. Only NID and 6-keto-PGF1α correlation persisted in SDN. In addition, brachial artery dysfunction
was negatively correlated with urinary albumin excretion and serum triglyceride in SDN patients.
Conclusions: Impaired brachial artery vasodilation was associated with reduced PGI2 and EET produc-
tion in older Chinese subjects with type 2 diabetes.
ing ischemic heart disease, cerebrovascular disease, peripheral
vascular disease, retinopathy, neuropathy and nephropathy, re-
sulting in organ and tissue damages in 50% to 75% of diabetic
patients 2,3. A large body of evidence has shown that vascular
endothelial dysfunction is an early event and vascular smooth
muscle pathology usually occurs later in the development of
diabetic vascular complications. Diabetic nephropathy, dened
by macroalbuminuria, is one of the most signicant long-term
microvascular complications in terms of leading to morbidity of
diabetic patients 4. Diabetes is also a common disease in order
populations. Almost 50% of patients diagnosed with type 2 dia-
betes are over 60 years of age 5. Hence, identication of biolog-
ical markers for evaluating vascular dysfunction is particularly
important in the management of senile diabetic patients.
Arachidonic acid (AA) and its metabolites are potent endothe-
lium-derived relaxing factors (EDRFs), playing a pivotal role
Research Articles
9Cardiology Plus 2016, Vol 1. No 2
in regulating vascular tone and tissue perfusion. AA is metab-
olized through three major enzymatic pathways. Cytochrome
P-450 (CYP) epoxygenases convert AA into four regioiso-
meric epoxyeicosatrienoic acids (EETs): 5,6-EET, 8,9-EET,
11,12-EET and 14,15-EET. Each EET regioisomer is quickly
hydrolyzed by epoxide hydrolase into four dihydroxyeicosa-
trienoic acids (DHETs) 6, 7. Cyclooxygenases metabolize AA
to synthesize prostacyclin (PGI2) which is rapidly converted
non-enzymatically to biologically inactive 6-keto-prostaglandin
F1α (6-keto-PGF1α) 8. AA is also converted by lipoxygenase
into leukotrienes and 12-hydroxyeicosatetraenoic acid (12-
HETE). EETs and PGI2 are potent vasodilators by activation
of the large conductance Ca2+-activated K+ channels and atten-
uation of intracellular Ca2+ concentration in vascular smooth
muscle cells 9-11. The eects of 12-HETE on vasoreactivity are
more complex and dependent on species and vessel beds. For
instance, 12-HETE can dilated the porcine coronary artery 11 but
constricts the canine renal arcuate artery 12. It has been shown
that a reduction of PGI2 biosynthesis was related to diabetic
vascular dysfunction 13 and an increase of 12-HETE generation
was observed in diabetic patients with early renal disease 14.
However, the correlation between AA metabolites and vascular
dysfunction in diabetic patients, particularly in Chinese elderly
with type 2 diabetes, has not been investigated. In this study, we
carried out a case-control study that enrolled 60 healthy elderly
volunteers, 78 senile diabetic patients without nephropathy and
58 senile diabetic patients with diagnosed nephropathy. We
found that endothelium-dependent and -independent vasodila-
tion in the brachial artery was impaired, which was accompa-
nied by decreased EET and PGI2 production in diabetic patients.
Diabetic brachial artery dysfunction was correlated with 14,15-
DHET before development of nephropathy. Most importantly,
there was a strong negative correlation between brachial artery
function and urinary albumin excretion in diabetic patients with
nephropathy. Hence, serum 14,15-DHET could serve a biologi-
cal marker for the evaluation of vascular function and a warning
sign of renal microvascular dysfunction in senile diabetic pa-
tients.
METHODS
Subjects: A case-control study was conducted with Han Chinese
patients with type 2 diabetes in our hospitals during the years
2007~2010. Type 2 diabetes and diabetic nephropathy were
diagnosed according to the American Diabetes Association Di-
agnostic Criteria (1997). Patients were split into two groups ac-
cording to their renal function: senile diabetic patients without
nephropathy (SD) and senile diabetic patients with nephropathy
(SDN). Patients with primary kidney diseases, heart failure,
stroke, coronary artery disease, severe hypertension and arterial
thrombotic diseases were excluded in order to avoid potential
confounding factors. Seventy-eight SD patients (39 male and 39
female, ages of 60 to 78 years) and fty-eight SDN patients (30
male and 28 female with 60 to 80 years of age) were recruited.
Age-matched volunteers (30 men and 30 women, ages of 60 to
70 years) free of systemic diseases known to aect vascular or
endothelial function, such as coronary artery disease, stroke,
diabetes, hypertension, hyperlipidemia, cancer, inflammatory
disease, active infection and trauma during at least three years
of continuous physical examination in our hospital and served
as healthy controls. The study protocol was approved by the
Medical Ethics Review Board of the Shanghai Public Health
Bureau and a written informed consent was obtained from all
participants prior to their participation in the study.
Laboratory examinations: Blood samples were obtained using
standard sterile technique from the antecubital vein. Serum
triglyceride (TG) (enzymatic colorimetric method), total choles-
terol (TC) (enzymatic colorimetric method), fasting blood glu-
cose (FBG) (hexokinase method) and hemoglobin A1c (HbA1c)
(high performance liquid chromatography) were measured
using a Hitachi Clinical Analyzer 7600 (Hitachi, High-Technol-
ogies Co., Japan).
A 24-hour urine collection test was performed. Urinary albumin
excretion (UAE) was given as the mean of 24-h urine excretions
and glomerular ltration rate (GFR) was estimated by 24-h cre-
atinine clearance. Diabetic nephropathy was dened as microal-
buminuria (UAE: 30~300 mg/24-h) or macroalbuminuria (UAE
> 300 mg/24-h) respectively, proteinuria > 0.5 g/24-h and/or
GFR < 60 mL/min/1.73m, based on the guidelines of American
Diabetes Association 15.
The concentrations of fasting serum 14,15-EET and 6-keto-PG-
F1α were measured using ELISA kits purchased from Detroit
R & D Inc. (Detroit, USA) and Cayman Chemical Co. (Ann
Arbor, USA), respectively.
Flow-mediated dilation (FMD) and nitroglycerine-induced
dilation (NID): FMD, endothelium-dependent vasodilation,
was evaluated as previously described 16. At least 5 h after
fasting, patients were required to lie at rest for 15 min at room
temperature (22°C) and FMD was assessed using a Vivid 7.0.4
Ultrasound System (GEhealthcare Co., USA) with a 14-Hz
linear transducer. The right brachial artery at 2.0~2.5 cm above
the elbow was scanned laterally. The average internal diameter
at end-diastole (D0) was measured and calculated from three
cardiac cycles. Subsequently, the pneumatic cuff was inflated
at 30 mm Hg above systolic blood pressure for 5 min, rapidly
released to 0 mm Hg, and the end-diastolic arterial diameter
(D1) was measured within 1 min. After a 15-min rest, 0.5 mg
nitroglycerin (NTG) was administrated sublingually in order to
assess endothelium-independent vasodilation (NID). Arterial
diameter (D2) was measured at 5 min after NTG administra-
tion. FMD and NID was calculated as [(D1-D0)/D0] × 100%.
Statistical analysis: Data are presented as mean±SE. Statistical
analyses were performed using PASW software for Windows
(version 18.0). One-way analysis of variance (ANOVA) was
used to compare the dierences amongst the three groups. Kras-
10
kal-Wallis post hoc test was applied for pairwise comparison
whenever the main eect of ANOVA was signicant. Spearman
rank correlation test was performed to determine the correlation
between two variables. Statistical significance was defined as
P<0.05.
RESULTS
The gender distribution was similar among the three groups.
The mean age of participants was 67.0 years (n=60) in health
elderly, 68.4 years (n=78, P=N.S. vs health elderly and SDN)
in SD and 70.5 years (n=58, P<0.05 vs health elderly and P=N.
S. vs DM) in SDN group. Duration of diabetic diagnosis was
7.7 years in the SD group and 16.9 years (P<0.05 vs SD) in
the SDN. Half of SD patients developed nephropathy within 9
years after diagnosis of diabetes, similar to a previous report
17. In healthy elderly subjects, serum TC, TG, HbA1c, FPF
and UAE levels were within normal ranges. SD patients had a
significantly decreased FPF and increased UAE in 24-h urine
collection, compared to healthy elderly controls. Moreover, FPF
and UAE were exacerbated in SDN patients (Table 1). Serum
TG, TC and HbA1c were signicantly elevated in SD patients,
accompanied by a remarkable reduction of serum 14,15-DHET
and 6-keto-PGF1α production, compared to those in healthy
elderly controls. Moreover, SDN patients had a worsened lipid
prole and a poor glycemic control as shown in Table 1.
Brachial arterial diameter at baseline, cuff release and after a
5-min sublingual administration of 0.5 mg nitroglycerine are
illustrated in Table 2. There was no significant difference in
baseline brachial artery inner diameter amongst the three study
groups. FMD and NID in the brachial artery were remarkably
reduced in SD patients (P<0.05 vs healthy elderly controls).
However, there was no further decline in SDN patients. These
results may suggest that impaired endothelium-dependent and
-independent vasodilation in the brachial artery preceded before
the onset of diabetic nephropathy in diabetic patients.
Multiple regression analysis demonstrated that in healthy elder-
ly controls, FMD was positively correlated with 6-keto-PGF1α,
but not with 14,15-DHET, TG, TC and HbA1c (Table 3). In
addition, NID was negatively correlated with FMD, which can
be explained by the limitation of maximal dilation of the vessel.
In SD patients, the correlation of FMD with 14,15-DHET and
6-keto-PGF1α was lost, but that of NID with 14,15-DHET and
6-keto-PGF1α was remained (Table 4). In SDN patients, sim-
ilarly, no correlation between FMD and 14,15-DHET or 6-ke-
to-PGF1α was distinguished, nor was NID with 14,15-DHET.
However, the correlation between NID and 6-keto-PGF1α was
observed in SDN patients (Table 5). Serum 14,15-DHET and
6-keto-PGF1α levels were negatively correlated with HbA1c,
TG, TC and UAE, but varied with dierent stages of the disease
(Table 4 and 5). In addition, there were a strong negative cor-
relation between UAE and NID and a strong positive correla-
tion between UAE and TG in SDN patients.
DISCUSSION
Cyclooxygenases are abundantly expressed in both endothelial
cells and smooth muscle cells in the vasculature, while CYP
epoxygenases are mainly expressed in vascular endothelial
cells 18, 19. As EDRFs, roles of EETs and PGI2 on the endotheli-
um-dependent vasodilation have been extensively investigated.
EET and PGI2 directly activate vascular potassium channels,
resulting in closure of voltage-gated Ca2+ channels, reduction
of intracellular Ca2+ concentration and vascular relaxation 18, 20.
It has been reported that PGI2 and EET biosynthesis was down
regulated in diabetic rats 20, 21. Pharmacological increase of EET
and PGI2 generations improved renal function in diabetic mice
22, 23. Clinical studies also demonstrated that long-term admin-
istration of PGI2 protected renal function in diabetic patients 24.
Up to date, very little is known about EET biosynthesis and its
relationship with vascular dysfunction in diabetes, practically
in senile human subjects with type 2 diabetes. Recently, a study
has shown that genetic variation of CYP epoxygenases was
associated with the early onset of human type 2 diabetes 25. In
this study, we found that both FMD and NID in brachial artery
were diminished, accompanied by a remarkable reduction in
serum 14,15-DHET and 6-keto-PGF1α levels in senile Chinese
patients diagnosed with type 2 diabetes. Furthermore, serum
14,15-DHET level was positively correlated with serum 6-ke-
to-PGF1α in senile diabetic patients, but negatively correlated
with HbA1c and TC in senile diabetic patients. It makes more
sense to our knowledge that an increase of EET and PGI2 bio-
synthesis and decrease of blood glucose and TC are benecial
to diabetic patients.
Group Age (years) nTG (mM) TC (mM) FPG (mM) HbA1c (%) UAE (µg/min) 14-15-DHET (ng/L) 6-keto-PGF1α (ng/L)
Elderly 67.03±3.81 60 1.34±0.48 5.04±0.82 4.87±0.49 5.37±0.31 3.69±2.85 2088.17±1232.0 110.68±76.73
SD 68.35±8.23 78 1.93±0.90* 5.60±1.14* 7.09±1.54*,6.76±1.01* 14.50±5.82* 1435.77±1097.43* 58.33±42.69*
SDN 70.57±7.16* 58 2.35±1.14* 5.88±1.13* 7.77±2.41*,† 7.32±1.11*,† 136.62±99.94*,† 1487.78±1230.97* 54.69±29.54*
SD: Senile diabetes, SDN: Senile diabetes with nephropathy, TG: triglyceride, TC: total cholesterol, FPG: fasting plasma glucose, HbA1c: hemoglo-
bin A1c, UAE: urinary albumin excretion. *: P<0.05, vs healthy elderly, †: P<0.05, vs. SD.
Table 1: Baseline subject characteristics of each group
Huang et al Reduced EET and PGI2 production in senile diabetic patients
11 Cardiology Plus 2016, Vol 1. No 2
Group nBaseline inner diameter (mm) Flow-mediated dilation (mm) Nitroglycerine-induced dilation (mm)
Elderly 60 3.82±0.61 11.87±7.55 19.87±7.94
SD 78 4.00±0.54 8.19±4.14* 15.87±5.51*
SDN 58 4.00±0.56 7.54±4.53* 15.09±6.53*
SD: Senile diabetes, SDN: Senile diabetes with nephropathy. *: P<0.05, vs. healthy elderly.
Table 2: Flow-mediated dilation and nitroglycerine-induced dilation in the brachial artery
NID 14,15-DHET 6-keto-PGF1α HbA1c TG TC UAE
FMD γ=-0.79
P=0.001
γ=0.16
P=0.22
γ=0.27
P=0.04
γ=-0.08
P=0.53
γ=0.01
P=0.94
γ=-0.19
P=0.16
γ=0.06
P=0.67
NID γ=0.14
P=0.92
γ=0.17
P=0.20
γ=-0.06
P=0.66
γ=-0.10
P=0.44
γ=-0.18
P=0.18
γ=0.03
P=0.81
14,15-DHET γ=0.20
P=0.12
γ=-0.06
P=0.63
γ=-0.08
P=0.57
γ=-0.12
P=0.35
γ=-0.09
P=0.52
6-keto-PGF1α γ=0.14
P=0.28
γ=-0.02
P=0.91
γ=-0.19
P=0.15
γ=0.09
P=0.50
HbA1c γ=-0.11
P=0.39
γ=0.04
P=0.76
γ=-0.11
P=0.40
TG γ=0.17
P=0.20
γ=0.05
P=0.74
TC γ=-0.11
P=0.41
FMD: ow-mediated dilation; NID: nitroglycerin-induced dilation, n=60.
NID 14,15-DHET 6-keto-PGF1α HbA1c TG TC UAE
FMD γ=-0.15
P=0.19
γ=0.12
P=0.28
γ=-0.15
P=0.19
γ=0.05
P=0.64
γ=-0.09
P=0.44
γ=-0.15
P=0.18
γ=-0.02
P=0.85
NID γ=0.3
P=0.009
γ=1.0
P=0.001
γ=0.04
P=0.70
γ=-0.10
P=0.40
γ=-0.002
P=0.98
γ=0.06
P=0.58
14,15-DHET γ=0.30
P=0.01
γ=-0.34
P=0.003
γ=-0.34
P=0.002
γ=-0.13
P=0.26
γ=0.03
P=0.78
6-keto-PGF1α γ=0.04
P=0.70
γ=-0.10
P=0.40
γ=-0.002
P=0.98
γ=0.06
P=0.58
HbA1c γ=0.42
P=0.0002
γ=0.21
P=0.07
γ=0.10
P=0.52
TG γ=0.43
P=1.0E-6
γ=0.21
P=0.64
TC γ=0.08
P=0.50
FMD: ow-mediated dilation; NID: nitroglycerin-induced dilation, n=78.
NID 14,15-DHET 6-keto-PGF1α HbA1c TG TC UAE
FMD γ=0.08
P=0.47
γ=0.16
P=0.17
γ=-0.008
P=0.94
γ=0.06
P=0.58
γ=-0.02
P=0.84
γ=-0.35
P=0.002
γ=-0.04
P=0.70
NID γ=-0.11
P=0.33
γ=0.28
P=0.01
γ=-0.09
P=0.42
γ=-0.05
P=0.66
γ=0.05
P=0.67
γ=-0.51
P=1.0E-8
14,15-DHET γ=0.07
P=0.56
γ=-0.02
P=0.85
γ=-0.02
P=0.90
γ=-0.03
P=0.77
γ=0.04
P=0.72
6-keto-PGF1α γ=0.03
P=0.79
γ=-0.09
P=0.45
γ=0.05
P=0.66
γ=-0.13
P=0.25
HbA1c γ=0.22
P=0.053
γ=0.09
P=0.43
γ=-0.01
P=0.94
TG γ=0.20
P=0.08
γ=0.30
P=0.009
TC γ=0.09
P=0.41
FMD: ow-mediated dilation, NID: nitroglycerin-induced dilation, n=58.
Table 3: Correlation of laboratory tests and brachial artery dilation in healthy elderly controls
Table 4: Correlation of laboratory tests and brachial artery dilation in senile diabetic patients
Table 5: Correlation of laboratory tests and brachial artery dilation in senile diabetic patients with nephrology
12
FMD is a commonly used methodology for evaluating the en-
dothelium-dependent vasodilation. We found that FMD in bra-
chial artery occurred only in healthy elderly but not in diabetic
patients; while NID in brachial artery was remained in diabetic
subjects. These results may imply that the endothelium-depen-
dent brachial artery vasodilation was impaired and its role was
compensated by the endothelium-independent mechanism in
senile diabetic patients. Interestingly, NID was independently
correlated with 14,15-DHET in diabetic patients before devel-
opment of nephropathy, and such correlation was lost in the
patients with nephropathy. On the other hand, the correlation
between 6-keto-PGF1α and NID lasted during the stage of
diabetic nephropathy. We believe that these differences may
account for biosynthesis ability or protein expression of CYP
and COX-2 enzymes in the vasculature of participants. Since
diabetic patients with nephropathy had a longer duration of the
disease in this study, our results may also suggest that EET-as-
sociated vasodilation in diabetes exists only a certain period of
time before total loss of endothelium function. It is worth noth-
ing that UAE was strong negatively correlated with NID, sug-
gesting that there is severe microvascular dysfunction in kidney.
CYP epoxygenases are abundantly expressed in vasculature and
kidney 26. Animal studies have shown the protective eects of
EETs on renal function in rats 27. Increase of CYP epoxygenase
expression attenuated nephropathy in diabetic mice 22. This is
the rst clinical study showing the relationship between AA me-
tabolites and vascular dysfunction in elderly diabetic patients.
Because renal dysfunction and cardiovascular complication
have higher mortality and worsened clinical outcomes 28, mon-
itoring of serum 14,15-DHET level may serve as a biomarker
for the evaluation of vascular function and provide a warning
sign for diabetic renal dysfunction in diabetic patients.
ACKNOWLEDGMENT
This work was supported by the Innovative Project of Medical
Science and Technology of PLA Nanjing Military Area Com-
mand [08A006] and the Key Project of the Health Bureau of
Hongkou District of Shanghai [0802-08(2008)98], P. R. China.
Y. H. designed project, organized research, analyzed data and
prepared the manuscript. T. L. designed project, discussed re-
sults and prepared the manuscript.
Conicts of interest
None declared
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