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Coenzyme Q(10) improves endothelial dysfunction of the brachial artery in Type II diabetes mellitus

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Coenzyme Q(10) improves endothelial dysfunction of the brachial artery in Type II diabetes mellitus

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We assessed whether dietary supplementation with coenzyme Q(10) improves endothelial function of the brachial artery in patients with Type II (non-insulin-dependent) diabetes mellitus and dyslipidaemia. A total of 40 patients with Type II diabetes and dyslipidaemia were randomized to receive 200 mg of coenzyme Q(10) or placebo orally for 12 weeks. Endothelium-dependent and independent function of the brachial artery was measured as flow-mediated dilatation and glyceryl-trinitrate-mediated dilatation, respectively. A computerized system was used to quantitate vessel diameter changes before and after intervention. Arterial function was compared with 18 non-diabetic subjects. Oxidative stress was assessed by measuring plasma F(2)-isoprostane concentrations, and plasma antioxidant status by oxygen radical absorbance capacity. The diabetic patients had impaired flow-mediated dilation [3.8 % (SEM 0.5) vs 6.4 % (SEM 1.0), p = 0.016], but preserved glyceryl-trinitrate-mediated dilation, of the brachial artery compared with non-diabetic subjects. Flow-mediated dilation of the brachial artery increased by 1.6 % (SEM 0.3) with coenzyme Q(10) and decreased by -0.4 % (SEM 0.5) with placebo (p = 0.005); there were no group differences in the changes in pre-stimulatory arterial diameter, post-ischaemic hyperaemia or glyceryl-trinitrate-mediated dilation response. Coenzyme Q(10) treatment resulted in a threefold increase in plasma coenzyme Q(10) (p < 0.001) but did not alter plasma F(2)-isoprostanes, oxygen radical absorbance capacity, lipid concentrations, glycaemic control or blood pressure. Coenzyme Q(10) supplementation improves endothelial function of conduit arteries of the peripheral circulation in dyslipidaemic patients with Type II diabetes. The mechanism could involve increased endothelial release and/or activity of nitric oxide due to improvement in vascular oxidative stress, an effect that might not be reflected by changes in plasma F(2)-isoprostane concentrations.
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In Type II (non-insulin-dependent) diabetes mellitus
the pathogenesis of vascular disease, its most com-
mon complication, remains unclear [1]. Endothelial
dysfunction reflects the disordered physiology of sev-
eral endothelium-derived vasoactive factors, in par-
ticular nitric oxide [2]. Endothelial dysfunction oc-
curs commonly in diabetes and is an early feature of
vasculopathy [3, 4]. Increased oxidative stress due to
the effects of hyperglycaemia and its sequelae is a
recognized feature of diabetes [5]. It might cause en-
dothelial dysfunction through the inactivation and
Diabetologia (2002) 45: 420±426
Coenzyme Q
10
improves endothelial dysfunction of the brachial
artery in Type II diabetes mellitus
G. F.Watts, D.A. Playford, K. D. Croft, N. C. Ward, T. A. Mori, V. Burke
Department of Medicine, University of Western Australia, Royal Perth Hospital, Perth, Australia
Ó Springer-Verlag 2002
Abstract
Aim/hypothesis. We assessed whether dietary supple-
mentation with coenzyme Q
10
improves endothelial
function of the brachial artery in patients with Type
II (non-insulin-dependent) diabetes mellitus and dys-
lipidaemia.
Methods. A total of 40 patients with Type II diabetes
and dyslipidaemia were randomized to receive
200 mg of coenzyme Q
10
or placebo orally for
12 weeks. Endothelium-dependent and independent
function of the brachial artery was measured as flow-
mediated dilatation and glyceryl-trinitrate-mediated
dilatation, respectively. A computerized system was
used to quantitate vessel diameter changes before
and after intervention. Arterial function was com-
pared with 18 non-diabetic subjects. Oxidative stress
was assessed by measuring plasma F
2
-isoprostane
concentrations, and plasma antioxidant status by oxy-
gen radical absorbance capacity.
Results. The diabetic patients had impaired flow-me-
diated dilation [3.8 % (SEM 0.5) vs 6.4% (SEM 1.0),
p = 0.016], but preserved glyceryl-trinitrate-mediated
dilation, of the brachial artery compared with non-di-
abetic subjects. Flow-mediated dilation of the brachi-
al artery increased by 1.6% (SEM 0.3) with coen-
zyme Q
10
and decreased by ±0.4% (SEM 0.5) with
placebo (p = 0.005); there were no group differences
in the changes in pre-stimulatory arterial diameter,
post-ischaemic hyperaemia or glyceryl-trinitrate-me-
diated dilation response. Coenzyme Q
10
treatment re-
sulted in a threefold increase in plasma coenzyme Q
10
(p < 0.001) but did not alter plasma F
2
-isoprostanes,
oxygen radical absorbance capacity, lipid concentra-
tions, glycaemic control or blood pressure.
Conclusion/interpretation. Coenzyme Q
10
supple-
mentation improves endothelial function of conduit
arteries of the peripheral circulation in dyslipidaemic
patients with Type II diabetes. The mechanism could
involve increased endothelial release and/or activity
of nitric oxide due to improvement in vascular oxida-
tive stress, an effect that might not be reflected by
changes in plasma F
2
-isoprostane concentrations.
[Diabetologia (2002) 45: 420±426]
Keywords Coenzyme Q
10
, endothelial function, nitric
oxide, diabetes.
Received: 14 August 2001 and in revised form: 15 November
2001
Corresponding author: G. F. Watts, PhD, MD, Department of
Medicine, University of Western Australia, Royal Perth Hos-
pital, GPO Box X2213, Perth, WA 6847, Australia.
e-mail: gfwatts@cyllene.uwa.edu.au
Abbreviations: CoQ, Coenzyme Q
10
; FMD, flow-mediated di-
latation; NMD, glyceryl-trinitrate-mediated dilatation;
ORAC, oxygen radical absorbance capacity
decreased synthesis of nitric oxide by reactive oxygen
species [6] such as superoxide.
While epidemiology suggests that conventional
antioxidant vitamins can benefit vascular disease,
the evidence from controlled clinical trials is less se-
cure [7], especially in diabetes [8]. Vitamin E supple-
mentation has not consistently been shown to im-
prove endothelial-dependent vasodilator tone in dia-
betic patients [9, 11]. Moreover, with vitamin C, the
only study reported in Type II diabetes was not place-
bo-controlled and involved acute intra-arterial ad-
ministration of this antioxidant [12].
Coenzyme Q
10
(CoQ) is a critical intermediate of
the mitochondrial electron transport chain that regu-
lates cytoplasmic redox potential and it can inhibit
superoxide generation by endothelial cells [13, 14].
CoQ is a more powerful antioxidant than vitamin E,
inhibiting its pro-oxidant activity [15, 16]. Its deficien-
cy can occur in diabetes in relation to impaired mito-
chondrial substrate metabolism [17] and increased
oxidative stress [6]. Mitochondrial CoQ deficiency
could be involved in the pathogenesis of Type II dia-
betes by impairing beta-cell function [18]. Low serum
CoQ concentrations have been negatively correlated
with poor glycaemic control and diabetic complica-
tions [19, 20]. Accordingly, some clinical trials have
shown that CoQ could improve glycaemic control
and blood pressure in diabetes [14, 18, 21, 22]. Hence,
CoQ could have a potential role in the treatment of
diabetes and its complications [14, 18, 23]. However,
to date no studies have reported the effects of CoQ
on vascular dysfunction or cardiovascular disease in
diabetes.
We report a placebo-controlled observation of the
effect of CoQ supplementation on vascular function
of the peripheral circulation in Type II diabetic pati-
ents. Endothelial function was quantitated as postis-
chaemic flow-mediated dilatation of the brachial ar-
tery using a new edge-detection software system that
increases the precision of measurements [24]. We
also measured potential changes in oxidative stress
by measuring plasma F
2
-isoprostanes and measuring
the oxygen radical absorbance capacity of plasma.
Subjects and methods
Subjects. A total of 40 patients with Type II diabetes diagnosed
by standard criteria and with dyslipidaemia were recruited
from the community. Dyslipidaemia was defined as a fasting
serum triglyceride of greater than 1.8 mmol/l or HDL choles-
terol of less than 1.0 mmol/l with total cholesterol of less than
6.5 mmol/l and a total cholesterol-to-HDL cholesterol ratio of
more than 4. Patients were excluded based on the following
criteria: age older than 75 years, BMI greater than 40 kg/m
2
,
history of myocardial infarction or stroke, insulin therapy,
smoking, macroalbuminuria, serum creatinine greater than
150 mmol/l, liver abnormalities, use of antioxidants or lipid-
regulating therapy, uncontrolled hypertension ( > 160/
90 mmHg), and treatment with angiotensin-converting en-
zyme inhibitors, calcium antagonists or aspirin. Volunteers un-
derwent a clinical examination, urinalysis and a 12-lead ECG.
The vascular function in the diabetic patients was compared
with 18 healthy, non-diabetic normolipidaemic subjects of sim-
ilar age [mean age 54 years (SD 12.0); cholesterol 5 mmol/l
(SD 0.4), HDL cholesterol 1.6 (0.3), triglyceride 0.9 (95 % CI
0.8, 1.1)].
Study design. This study is part of a larger study examining the
effects of CoQ and lipid-regulating therapies on vascular func-
tion of peripheral arteries measured by several techniques. We
report on the effect of CoQ monotherapy on postischaemic di-
lation of the brachial artery. Eligible patients entered a run-in
period of 6 weeks during which they were instructed to con-
sume an isocaloric fat-modified diet of constant antioxidant
composition. They then underwent the brachial artery reactiv-
ity test described below, after which they were randomized
double-blind to treatment with either CoQ (Blackmores, Syd-
ney, NSW, Australia) or matching placebo in a trial of
12 weeks duration. Coenzyme Q
10
(200 mg) was taken as two
50 mg capsules orally twice a day. Volunteers were interviewed
every 2 weeks to assess their compliance with therapeutic units
and brachial artery reactivity was re-studied 12 weeks after
randomization. The Ethics Committee of the Royal Perth
Hospital approved the study and all volunteers gave their writ-
ten consent.
Laboratory methods. Venous blood was collected after a 12 h
fast at baseline and at 12 weeks. Serum total cholesterol, tri-
glyceride and HDL cholesterol were measured using enzymat-
ic, colorimetric methods (Boehringer Mannheim, Mannheim,
Germany) on a Hitachi 917 biochemical analyser (Hitachi, To-
kyo, Japan). High-density lipoprotein cholesterol was mea-
sured after precipitation of apolipoprotein B-100 (apoB) con-
taining lipoproteins with dextran sulphate. Low-density lipo-
protein cholesterol was estimated by the Friedewald formula
and by a direct assay when triglycerides were more than
3.5 mmol/l. The particle size of LDL was estimated by non-de-
naturing gel electrophoresis. Glycated haemoglobin (HbA
1c
)
was measured by high performance liquid-chromatography
(HPLC, BioRad Laboratories, Sydney, Australia). Plasma glu-
cose and insulin were assayed using an enzymatic method
(Boehringer) and an automated immuno-enzymometric assay
(Tosoh, Kyobashi, Tokyo, Japan), respectively. Serum and uri-
nary creatinine were measured by the modified Jaffe reaction.
Total serum CoQ concentration was assayed by reverse-phase
high performance liquid-chromatography using electrochemi-
cal detection [25]. Plasma F
2
-isoprostanes were analysed using
gas-chromotography mass-spectrometry with electron capture
negative chemical ionization [26]. Plasma oxygen radical ab-
sorbance capacity (ORAC) was measured using a fluorescent
assay using a Trolox standard [27].
Brachial artery ultrasonography. Brachial artery ultrasonogra-
phy was carried out [28]. Briefly, a 12-megahertz transducer
connected to an Acuson Aspen ultrasound (Acuson, Mountain
View, Calif, USA) and fixed in position by a stereotactic clamp
5 to 10 cm proximal to the ante-cubital crease was used to im-
age the brachial artery. Images were recorded before and after
vasodilatory stimuli and recorded on s-VHS videotape (Sony
MQSE 180). Continuous ECG monitoring was done in all
studies. Reactive hyperaemia of the brachial artery was in-
duced after release of a pneumatic tourniquet placed around
the left forearm and inflated to 50 mmHg above systolic blood
pressure for 5 min. Pulse wave Doppler flow velocities were
used to derive flow rate (ml/min) pre-reactive and post-reac-
G. F. Watts et al.: CoQ improves endothelial function in diabetes 421
tive hyperaemia. After the brachial artery diameter returned
to baseline 400 mg glyceryl trinitrate was administered sublin-
gually to assess endothelium-independent vasodilatory re-
sponse. All images obtained were assessed blindly by two inde-
pendent observers and only pairs of scans that were of consis-
tently acceptable quality were included in this analysis. Analy-
sis of flow-mediated dilatation (FMD) and glyceryl-trinitrate-
mediated dilatation (NMD) of the brachial artery was carried
out using a semi-automated edge detection software system
[24] and operated by an experienced observer, who was blind-
ed to the treatment group assignment. Responses were calcu-
lated as percentage change in brachial artery diameter from
baseline. The analytical (intra-observer) coefficient of varia-
tion of the computerized technique is 6.7 % compared with
32.5 % using ultrasonic callipers, a more conventional visual
estimation. The resolving power of the method tested on
`phantom arteries' is 8.3 mm.
Statistical methods. Data were analysed parametrically after
logarithmic transformation of variables where appropriate.
Discrete variables were compared by Chi-square test. Treat-
ment effects were analysed using general linear models with
adjustments for baseline values and resting brachial artery di-
ameter. Association between variables were examined by lin-
ear regression methods. Statistical significance was defined at
a p value of less than 0.05.
Results
The diabetic patients were mostly middle-aged men
and were on average, overweight, normotensive, in
good glycaemic control and had typical diabetic dys-
lipidaemia. Of the 40 patients randomized, 39 com-
pleted the study and one withdrew due to an inciden-
tal illness. High quality ultrasound images were ob-
tained in all patients randomized to CoQ. However,
satisfactory image quality was not obtained in ultra-
sound scans from four patients randomized to place-
bo. Thus, our analysis refers to the residual 35 diabet-
ic patients. Their characteristics did not differ from
those withdrawn from the study.
Plasma F
2
-isoprostanes were not different be-
tween the diabetic patients and the non-diabetic con-
trol subjects [1245 mmol/l (95 % CI 1075, 1442) vs
1310 (1085, 1583), p = 0.670]. However, plasma
ORAC was lower in the diabetics patients than in
the control subjects [3766 mmol/l (95% CI 3476,
4081) vs 4729 (4551, 4914) p = < 0.001].
Compared with the control subjects, the diabetic
patients overall had lower post-ischaemic FMD of
the brachial artery [3.8 % (SEM 0.5) vs 6.4 (1.0),
p = 0.016] but similar NMD responses [16.5 % (SEM
0.9) vs 18.5 (1.7), p = 0.291].
No differences were shown in the characteristics
(Table 1) between patients randomized to placebo
and CoQ treatment (p > 0.05), except for higher
baseline plasma CoQ concentrations (p = 0.03) in
the CoQ group. Only four patients in the study took
metformin, one in the placebo and three in the CoQ
group. The plasma glucose immediately before ultra-
sonography did not differ (p = 0.20) between the
groups (Table 1).
The changes in baseline diameter, reactive hyper-
aemia, FMD and NMD of the brachial artery in the
CoQ were compared with the placebo group (Ta-
ble 2). There was an improvement in FMD of the bra-
chial artery in the CoQ compared with the placebo
group, without changes or differences in baseline ar-
terial diameter, reactive hyperaemia or NMD. In an
analysis with absolute FMD (mm) at 12 weeks as the
dependent variable, there was still a favourable treat-
ment effect of CoQ (p = 0.002) after adjusting for
baseline brachial artery diameter (mm) at 12 weeks
and pre-randomization percentage FMD response.
This analysis together with the lack of significant
change in resting brachial artery diameter (Table 2)
demonstrates that the favourable effect of CoQ on
percentage FMD response was independent of chan-
ges in basal brachial artery tone. There were no dif-
ferences between the groups in the plasma glucose
concentration immediately before ultrasonography
post-intervention [8.2 mmol/l (SEM 0.8) for CoQ vs
7.3 mmol/l (0.7) for placebo, p = 0.43].
Treatment with CoQ was associated with an in-
crease in plasma CoQ concentrations, from
G. F. Watts et al.: CoQ improves endothelial function in diabetes422
Table 1. Clinical, biochemical and vascular characteristics of
the patients in the placebo and CoQ groups at baseline
Characteristics Placebo group CoQ group
n (male/female) 13/2 18/2
Age (years) 54.1 (10.4) 52.7 (6.2)
BMI (kg/m
2
) 31.3 (5.4) 29.9 (3.3)
SBP (mmHg) 139.1 (15.1) 128.0 (18.4)
DBP (mmHg) 81.0 (5.8) 75.8 (9.3)
Glucose (mmol/l) 6.9 (2.1) 8.2 (2.7)
HbA
1c
(%) 6.2 (0.8) 6.9 (1.4)
Insulin (mU/l) 15.1 (7.4) 12.2 (5.4)
Cholesterol (mmol/l) 5.3 (0.6) 5.3 (0.9)
Triglyceride (mmol/l) 2.5 (2.1, 3.0) 2.0 (1.7, 2.5)
HDL-cholesterol (mmol/l) 1.00 (0.08) 0.95 (0.15)
LDL-cholesterol (mmol/l) 3.2 (0.7) 3.2 (0.9)
LDL size (nm) 25.3 (0.8) 25.0 (0.8)
Coenzyme Q
10
(mmol/l) 1.2 (0.3) 1.5 (0.3)*
ORAC activity (mmol/l) 3638 (3270, 4046) 3723 (3275, 4233)
Plasma F
2
-isoprostanes
(pmol/l) 1297 (1023, 1643) 1102 (892, 1361)
Brachial artery:
Baseline diameter (mm) 4.3 (0.6) 4.2 (0.5)
Resting blood flow (ml/min) 186.6 (72.8) 205.9 (113.7)
Reactive hyperaemia (%) 462.2 (239.8) 431.9 (254.7)
Flow-mediated dilatation
(%) 4.5 (3.0) 2.8 (3.0)
Nitrate-mediated dilatation
(%) 16.9 (6.4) 16.3 (5.2)
Values are means (SD) or geometric means and 95 % CI
*p = 0.03 vs placebo group
1.3 mmol/l (SEM 0.1) to 4.8 (0.4), p < 0.001; however,
there were no alterations (p > 0.05) in plasma F
2
-iso-
prostanes, plasma ORAC activity, glucose, HbA
1C
,
plasma lipids, blood pressure or other variables (Ta-
ble 1). Changes in plasma CoQ concentrations were
not correlated with the changes in plasma F
2
-isopros-
tanes. The FMD of the brachial artery increased with
CoQ alone from 2.8 % (SEM 0.7) to 4.4 % (0.5),
p < 0.001 but the post-treatment response tended to
stay lower (p = 0.07) than the values for the non-dia-
betic control group. There was no correlation be-
tween the change in FMD and change in other vari-
ables in the CoQ group. In data pooled from both pa-
tient groups, improvement in FMD was only corre-
lated with treatment group assignment to CoQ.
Discussion
Our randomized, double-blind study shows a favour-
able effect of oral CoQ supplementation on endothe-
lial dysfunction of the peripheral circulation in pati-
ents with Type II diabetes. Coenzyme Q
10
improved
abnormal endothelium-dependent vasodilator tone
of the brachial artery without altering the vasodilato-
ry response to the endothelium-independent agonist
glyceryl trinitrate. This favourable effect of CoQ was
independent of changes in resting brachial artery di-
ameter. The improvement in endothelial function
also occurred in the presence of dyslipidaemia and
was not related to changes in plasma F
2
-isoprostanes,
glycated haemoglobin or blood pressure.
That oxidative stress is increased in diabetes is well
supported by experimental and clinical observations
[5, 6, 11, 29, 30]. Oxidative stress occurs in diabetes
as a consequence of several mechanisms related to
hyperglycaemia [5, 6]. These include accumulation
of AGE, activation of the polyol pathway and stimu-
lation of protein kinase C activity. Diabetes-induced
generation of reactive oxygen species, in particular
superoxide, decreases the expression of nitric oxide
synthase and inactivates nitric oxide [6, 31]. Vascular
oxidative stress could explain why our patients had
impaired FMD of the brachial artery with preserved
vasodilation to glyceryl trinitrate. Unexpectedly, our
patients did not show evidence of increased oxidative
stress, as measured by plasma concentrations of F
2
-
isoprostanes. Plasma F
2
-isoprostanes reflect non-en-
zymic, free radical induced lipid peroxidation and
might not be sensitive to increases in oxidative stress
at the vascular wall. Previously reported increases in
plasma F
2
-isoprostanes and their diminution in diabe-
tes with antioxidant vitamins referred to patients with
poorer glycaemic control than our study group [29,
30]. We found that plasma antioxidant capacity was
decreased in our patients in agreement with previous
reports showing that diabetic patients have decreased
plasma concentrations of antioxidant vitamins [32].
However, low plasma ORAC was not corrected by
CoQ supplementation, suggesting that CoQ might
not contribute to plasma antioxidants measured by
this assay. A dissociation between changes in endo-
thelial function and plasma F
2
-isoprostane concentra-
tions was found using antioxidant vitamin supple-
mentation in non-diabetic subjects [33]. Our patients
were dyslipidaemic and it is possible that increased
plasma concentrations of lipoprotein remnants,
small-dense LDL and low HDL cholesterol might
have contributed to endothelial dysfunction in the
absence of a systemic increase in oxidative stress [6].
There is evidence in Type II diabetes for and
against improvement in vasodilator function of fore-
arm resistance arteries in response to the muscarinic
agonist acetylcholine with vitamin E supplementa-
tion [10, 11]. One positive study using a vitamin E an-
alogue was not placebo controlled but did show re-
duction in plasma F
2
-isoprostanes in a small number
of patients [11]. Vitamin E supplementation was re-
ported to improve forearm microcirculatory function
in a larger sample of Type II diabetic patients in a
well-controlled trial [10]. Improvement in methacho-
line-mediated vasodilator function of forearm resist-
ance vessels was also reported in Type II diabetes fol-
lowing the intra-arterial administration of vitamin C
[12]. However, that study used a small sample size, in-
volved an acute intervention, and did not use a place-
bo arm. A recent report has shown that intra-arterial
administration of the powerful antioxidant a -lipoic
acid improved forearm blood flow responses to ace-
tylcholine to the same extent as ascorbic acid in pati-
ents with Type II diabetes [34]. The greatest benefit
was seen in patients with low-plasma concentration
of CoQ, supporting an important role of CoQ in vas-
cular endothelial dysfunction in Type II diabetes. We
G. F. Watts et al.: CoQ improves endothelial function in diabetes 423
Table 2. Changes in baseline diameter, reactive hyperaemia, flow-mediated dilatation (FMD) and nitrate-mediated dilatation
(NMD) of the brachial artery in the diabetic patients treated with placebo or CoQ supplementation for 12 weeks
Variable Placebo group CoQ group p value
Change in baseline artery diameter (mm) 0.05 (0.09) ±0.02 (0.08) 0.611
Change in resting blood flow (ml/min) ±43.3 (19.7) 20.6 (30.4) 0.136
Change in reactive hyperaemia (%) 85.0 (38.6) ±27.3 (84.5) 0.316
Change in FMD (%) ±0.4 (0.5) 1.6 (0.3) 0.005
Change in NMD (%) ±0.1 (1.4) 0.4 (1.2) 0.771
Values are means SEM
have extended previous reports by investigating in-
tervention with the antioxidant CoQ in a larger sam-
ple of patients and in a peripheral conduit artery. In
contrast to forearm microcirculatory blood flow re-
sponses to acetylcholine, post-ischaemic FMD of the
brachial artery has been shown to be a surrogate for
the coronary circulation and to predict coronary
events in patients with angina [35, 36].
The beneficial properties of CoQ could relate not
only to its antioxidant effect [15, 16], but also to im-
provements in glycaemic control [18] and blood pres-
sure [14]. Coenzyme Q
10
is a powerful antioxidant
that might decrease superoxide generation from en-
dothelial cells [13, 14]. Since our patients remained
dyslipidaemic, their increased plasma concentration
of small-dense LDL and low HDL would have con-
tributed to endothelial dysfunction [6]. By decreasing
vascular oxidative stress, CoQ could decrease the ox-
idative modification of LDL and HDL in the seques-
tered environment of the arterial wall, thereby in-
creasing the synthesis and/or action of endogenously
derived nitric oxide [6, 37, 38]. This effect might par-
ticularly extend to triglyceride-rich lipoproteins in
the post-prandial phase, when oxidative stress could
be maximal in diabetes [39]. Coenzyme Q
10
supple-
mentation has been reported to improve glycaemic
control [14, 18, 21, 22] and blood pressure [22] in pati-
ents with diabetes. However, along with other studies
[40, 41], we found no evidence to support this finding.
Other potential mechanisms whereby CoQ could
have improved endothelial function in the brachial
artery involve reduction in the cellular levels of asym-
metric dimethyl-arginine and AGEs [31, 42], as well
as an increase in the bioavailability of tetrahydrobi-
opterin [43] and glutathione [44]. Normalization of
mitochondrial superoxide production could be cen-
tral to these mechanisms and to an anti-inflammatory
effect of CoQ [45].
We did not rigorously study the mechanism of ac-
tion of CoQ with pharmacological agents, such as
acetylcholine with and without N
G
-monomethyl-l-
arginine. Post-ischaemic FMD of human conduit ar-
teries has predominately been shown to be mediated
by nitric oxide, although studies to date have mostly
referred to the radial artery [46]. We cannot infer
that the vascular benefit of CoQ extends to microcir-
culatory function, where the mediators of shear-stress
induced increase in blood flow could be different
from conduit vessels [4]. Because NMD of the brachi-
al artery was tested maximally with a high dose of
GTN, we cannot strictly exclude that our diabetic pa-
tients had non-endothelial vascular dysfunction, and
that this abnormality improved with CoQ. Acute hy-
perglycaemia has been shown to impair FMD of the
brachial artery [47] and we did not study patients at
isoglycaemia. However, at the time of ultrasound, pa-
tients were on average near-normoglycaemic and
there was no difference in blood glucose concentra-
tions before and after intervention. Metformin has
also been reported to improve brachial artery endo-
thelial function in diabetes [48], but the number of pa-
tients included in our study on this agent were small
and did not differ between intervention and control
groups. The clinical relevance of the small but signifi-
cant 1.6 % increase in FMD in our patients with CoQ
supplementation is not clear, given that FMD is only
weakly correlated with coronary responses and that
NMD did not change with treatment. We were able
to detect a small improvement in FMD, however, be-
cause of the enhanced precision of our computerized
method for assessing luminal diameter changes.
If our findings reflect the favourable effect of CoQ
on the bioavailability and action of nitric oxide, they
have implications for the prevention and reversal of
atherogenesis, procoagulopathy and myocardial dys-
function in diabetic patients [2, 4, 6]. That a benefit
in endothelial function was seen in the presence of di-
abetic dyslipidaemia without complete restoration of
FMD to normal, raises the possibility of further in-
vestigating the synergistic effects of CoQ with other
agents that could improve vascular function in diabe-
tes, such as angiotensin-converting enzyme inhibi-
tors, fish-oils and lipid regulators [4, 6].
Acknowledgements. This study was supported by research
grants from Diabetes Australia, The National Health and
Medical Research Council of Australia and The Medical Re-
search Foundation, Royal Perth Hospital. We thank Black-
mores (Australia) for providing the CoQ and matching place-
bo and Professor J. Best for estimating the particle size of
LDL. We are also grateful to the research nurses and technical
staff of the University Department of Medicine, in particular
Ms M-A Powell, for her excellent assistance in carrying out
the study. We acknowledge the assistance of Ms L. Rich and
Mr R. Woodman in assuring the quality of the analyses of the
ultrasound scans.
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... The present study showed that an average of 12 weeks were used for each clinical trial excluding a randomized, double-blind, phase II-a placebo-controlled, clinical trial conducted by Rodríguez-Carrizalez et al. [49] on retinopathy that lasted for approximately 6 months. Four of these clinical trials revealed that coenzyme Q10 improved endothelial function thereby reducing microvascular complications of DM, including vasculopathy as reported by Watts et al. [37], Hamilton et al. [40], Hosseinzadeh-Attar et al. [41] and Al-Kuraishy et al. [42]. ...
... In details, several studies conducted between 2002 and 2019 were reviewed based on their contributions in reference to effects of coenzyme Q10 on vasculopathy. Studies conducted by Watts et al. [37] in 2002, Playford et al. in [38] 2002 and Hamilton et al. [40] in 2009 revealed that there was improved endothelial function of the conduit arteries after exogenous supplementation with coenzyme Q10. The study by Playford et al. [38] in 2002 involved randomly assigning an oral dosage of 100 mg CoQ10 twice a day and 200 mg fenofibrate each morning for 12 weeks. ...
Article
Full-text available
Results from investigations about the effect of coenzyme Q10 supplementation on diabetes mellitus and its related complications have varied and are slightly inconsistent. This review study aims at highlighting key points in several clinical trials, the potential effect of coenzyme Q10 on glycaemic biomarkers in diabetes mellitus alongside its complications while spotting out several similarities and differences within clinical trials. Twenty-six articles from well-known databases that provided details on clinical trials between 1999 and 2020were reviewed. In summarized tables, the articles provided information on the effects of coenzyme Q10 supplementation on glycaemic control of diabetes mellitus and its complications. Four of thirteen studies reported no significant changes in metabolic parameters of diabetes mellitus; three results from these studies reported that there might be improved glycaemic control especially when coenzyme Q10 is taken in combination with conventional antidiabetic medicines. Results from the other thirteen clinical studies on main outcomes of diabetic complications also varied. Eight of these clinical trials revealed that coenzyme Q10 improved endothelial function thereby reducing vasculopathy and nephropathy of diabetes mellitus complications, while two double-blind placebo-controlled clinical trial showed significant improvement in neuropathy and retinopathy symptoms of diabetes mellitus, respectively. It was observed that the clinical trials with the lowest population sizes concluded that coenzyme Q10 may contribute to potential long-term benefits in the treatment of type 2 diabetic patients and its complications; however, more randomized and large-sample-size trials of coenzyme Q10 for type 2 diabetes mellitus are needed in the nearby future.
... The present study showed that an average of 12 weeks were used for each clinical trial excluding a randomized, double-blind, phase II-a placebo-controlled, clinical trial conducted by Rodríguez-Carrizalez et al. [49] on retinopathy that lasted for approximately 6 months. Four of these clinical trials revealed that coenzyme Q10 improved endothelial function thereby reducing microvascular complications of DM, including vasculopathy as reported by Watts et al. [37], Hamilton et al. [40], Hosseinzadeh-Attar et al. [41] and Al-Kuraishy et al. [42]. ...
... In details, several studies conducted between 2002 and 2019 were reviewed based on their contributions in reference to effects of coenzyme Q10 on vasculopathy. Studies conducted by Watts et al. [37] in 2002, Playford et al. in [38] 2002 and Hamilton et al. [40] in 2009 revealed that there was improved endothelial function of the conduit arteries after exogenous supplementation with coenzyme Q10. The study by Playford et al. [38] in 2002 involved randomly assigning an oral dosage of 100 mg CoQ10 twice a day and 200 mg fenofibrate each morning for 12 weeks. ...
Article
Full-text available
Results from investigations about the effect of coenzyme Q10 supplementation on diabetes mellitus and its related complicationshave varied and are slightly inconsistent. This review study aims at highlighting key points in several clinical trials, the potentialeffect of coenzyme Q10 on glycaemic biomarkers in diabetes mellitus alongside its complications while spotting out severalsimilarities and differenceswithin clinical trials. Twenty-six articles from well-known databases that provided details on clinicaltrials between 1999 and 2020were reviewed. In summarized tables, the articles provided information on the effects of coenzymeQ10 supplementation on glycaemic control ofdiabetes mellitus and its complications. Four of thirteen studies reported no significantchanges in metabolic parameters of diabetes mellitus; three results from these studies reported that there might be improvedglycaemic control especially when coenzyme Q10 is taken in combination with conventional antidiabetic medicines. Results fromthe other thirteen clinical studies on main outcomes of diabetic complications also varied. Eight of these clinicaltrials revealed thatcoenzyme Q10 improved endothelial function thereby reducing vasculopathy and nephropathy of diabetes mellitus complications,while two double-blind placebo-controlled clinical trial showed significant improvement in neuropathy and retinopathy symptomsof diabetes mellitus, respectively. It was observed that the clinicaltrials with the lowest population sizes concluded that coenzymeQ10 may contribute to potential long-term benefits in the treatment of type 2 diabetic patients and its complications; however, morerandomized and large-sample-size trials of coenzyme Q10 for type 2 diabetes mellitus are needed in the nearby future.
... КоQ10безпечний і ефективний додатковий засіб для лікування широкого спектра серцево-судинних захворювань, використання якого не тільки поліпшує клінічні результати, а й дозволяє знизити сумарні витрати на лікування [2,3,26,27]. У дослідженнях установлено поліпшення функціональної потужності, ендотеліальної функції та скоротливості лівого шлуночка без будь-яких побічних ефектів [37,40,41,46]. ...
... Певна роль у патогенезі ЦД 2-го типу відводиться нестачі КоQ10, наявної при діабеті, що супроводжується погіршенням метаболізму мітохондрій, а також підвищенням ступеня вираженості окиснювального стресу [34]. Слід зазначити, що крім глюкозотоксичності наявна при ЦД ліпотоксичність знижує експресію в β-клітинах генів ферментів, зокрема глюкокінази і гліцерин-3-дегідрогенази, які опосередковують недостатність глюкозостимульованої секреції інсуліну, особливо в умовах відносної недостатності у них КоQ10 [41]. Це ще раз підтверджує необхідність застосування у хворих на ЦД 2-го типу екзогенного КоQ10 для поліпшення функціональної активності β-клітин і стану вуглеводного обміну. ...
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В статье изложены результаты анализа литературы, посвященные обсуждению преимуществ и потенциальных возможностей альфа-липоевой кислоты и коэнзима Q10 (убихинон) у пациентов с кардиоваскулярными заболеваниями, хроническими диффузными заболеваниями печени, сахарным диабетом и другими метаболическими состояниями. Сегодня ведется активный поиск дополнительных источников, способствующих улучшению углеводного и липидного обмена, метаболических и энергетических процессов в организме, которые повышают устойчивость сердечно-сосудистой системы и печени к различным нарушениям и патологическим воздействиям, а также способствуют восстановлению функций различных органов при их повреждениях. В Украине комбинация альфа-липоевой кислоты и коэнзима Q10 представлена отечественным комплексом Липофарм от компании «Фармаком».
... Secondly, the alleviation of heat-stress-induced endothelial dysfunction might be the first explanation for increased TBF in our study and CoQ10 could be accumulated in the vascular endothelium, following an intravenous administration, and induced NO-dependent aortic vasodilatation in rats (Kozaeva et al. 2017). An earlier study also reported that dietary CoQ10 supplements ameliorated diabetes mellitus-induced endothelial dysfunction of the brachial artery in humans (Watts et al. 2002). Improving the endothelial functions in oxidative stress conditions could be explained via its antioxidant capability which indirectly increases NO bioavailability through inactivation of superoxide anion radicals and inhibition of peroxynitrite formation (highly Fig. 4 Alterations in plasma levels of testosterone (T; ng/mL; A), estradiol (E2; pg/mL; B), serum nitric oxide levels (NOMs, µmol/L; C), follicle-stimulating (FSH; ng/mL; D), and luteinizing hormones (LH; ng/mL; E) in male bucks that received coenzyme Q10 com-pared to control group. ...
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Oxidative stress (OS) is brought on by heat stress (HS), which weakens antioxidant defense and initiates OS. Since mitochondria are the primary source of reactive oxygen species (ROS), HS-mediated OS may be lessened by targeting mitochondria with particular antioxidants. The purpose of this study was to investigate the effect of oral coenzyme Q10 (CoQ10) supplementation on the reproductive performance of goat bucks under HS conditions. Ten mature bucks were randomly separated into two groups and housed in an environment with a high-temperature humidity index (THI: 88.3 to 94.8; summer season). The first group (n = 5) got the baseline diet while the second group (n = 5) received supplemental oral CoQ10 (3 mg/kg BW; CoQ10 group) daily for six weeks. Testicular blood flow parameters (TBF), testicular volume (TV) and echogenicity (TE), nitric oxide (NO), seminal alanine aminotransferase (ALT) and catalase (CAT) activities, total antioxidant capacity (TAC), malondialdehyde (MDA) content, and semen quality traits were all measured. The examinations started a week before (W-1), on the first supplementation day (W0), and weekly for eight consecutive weeks (W1-W8). There were marked (P < 0.05) increases in TBF (W3-W6) and TV, and a decrease in TE (W3-W5) in the CoQ10 group compared to the CON group. Similarly, testosterone (T) and NO levels (W3-W5) in the CoQ10 group were higher (P < 0.05) than those of the control group. The CoQ10 group demonstrated significant (P < 0.05) increases in seminal CAT (W4-W8) and TAC (W2-W6) activities and decreases in ALT (W4-W7) activity and MDA (W5-W8) concentration as compared to the control group. The CoQ10 group showed improvements (P < 0.05) at W3-W6 for sperm progressive motility, viability, and normal morphology and at W6-W8 for sperm concentration. In conclusion, oral CoQ10 supplementation improved testicular hemodynamics, testosterone production, semen quality, and antioxidant capacity in goat bucks during summer heat stress conditions.
... In vivo, CoQ10 reduced superoxide production and recouples mitochondrial oxidative phosphorylation [135]. In patients with type 2 diabetes, CoQ10 quenches ROS, reduces superoxide production and improves endothelial function by increasing brachial artery FMD [136]. CoQ 10 plays an important role in cellular ATP production but is decreased in cardiovascular disease and influenza infected patients. ...
Article
Full-text available
COVID-19 is an endothelial disease. All the major comorbidities that increase the risk for severe SARS-CoV-2 infection and severe COVID-19 including old age, obesity, diabetes, hypertension, respiratory disease, compromised immune system, coronary artery disease or heart failure are associated with dysfunctional endothelium. Genetics and environmental factors (epigenetics) are major risk factors for endothelial dysfunction. Individuals with metabolic syndrome are at increased risk for severe SARS-CoV-2 infection and poor COVID-19 outcomes and higher risk of mortality. Old age is a non-modifiable risk factor. All other risk factors are modifiable. This review also identifies dietary risk factors for endothelial dysfunction. Potential dietary preventions that address endothelial dysfunction and its sequelae may have an important role in preventing SARS-CoV-2 infection severity and are key factors for future research to address. This review presents some dietary bioactives with demonstrated efficacy against dysfunctional endothelial cells. This review also covers dietary bioactives with efficacy against SARS-CoV-2 infection. Dietary bioactive compounds that prevent endothelial dysfunction and its sequelae, especially in the gastrointestinal tract, will result in more effective prevention of SARS-CoV-2 variant infection severity and are key factors for future food research to address.
... Furthermore, Mediterranean diet for 18 months increased FMD without affecting the blood glucose or HbA1c level in diabetic and prediabetic patients [66•, 67]. In our randomized crossover trial, 4-week intervention with a fish-based diet significantly improved vascular endothelial function evaluated by strain-gauge plethysmography without affecting the blood glucose or insulin level [72]. In other randomized controlled trials, also, poly-unsaturated fatty acids, such as EPA and krill oil [73,74], soy germ [75], and supplements, such as coenzyme Q10 [76], improved vascular endothelial function in diabetic and prediabetic patients without changes in the blood glucose level. ...
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Purpose of Review This review aims to summarize the literature on periodontal disease and nutrition, focusing on endothelial dysfunction in diabetic patients, and their impact on oral health. Recent Findings Environmental factors, including smoking, obesity, and diabetes are well-known risk factors for the onset and progression of the periodontal disease. Indeed, dietary factors show an association with periodontal health through local and systemic environments. In addition, systemic factors, such as insulin resistance and diabetes, may have an important role in the periodontal health. Although molecular mechanisms underlying this are not fully understood, endothelial dysfunction mainly by hyperglycemia and/or chronic inflammation may explain the association between periodontal status and nutrition. In this paper, we reviewed recent progress in this field and propose the potential impact of nutritional intervention in the oral health from the viewpoint of endothelial function. Summary It is expected to become increasingly important to understand the pathology of diabetes-related periodontal disease and consider nutritional approaches with vascular dysfunction in mind for its prevention and treatment. Further accumulation of evidence is anticipated for the future.
... It has been observed that patients with T2DM have low levels of CoQ 10 in their plasma, and supplementation with CoQ 10 and selenium in the same study as referred to above also appeared to reduce formation of advanced glycated products (Alehagen et al., 2020a). Furthermore, supplementation with CoQ 10 alleviated endothelial dysfunction associated with diabetic complications (Hamilton et al., 2009;Watts et al., 2002). Hence, in the population given coenzyme Q 10 , combined with selenium, Alehagen et al. observed a significant decrease in the plasma concentrations of von Willebrand factor and PAI-1 (plasminogen activator inhibitor-1), which was interpreted as a normalization of endothelial function in the supplemented subjects as compared with those given placebo (Alehagen et al., 2020b). ...
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Coenzyme Q10 (CoQ10) is an essential component of the mitochondrial electron transport chain. It is also an antioxidant in cellular membranes and lipoproteins. All cells produce CoQ10 by a specialized cytoplasmatic-mitochondrial pathway. CoQ10 deficiency can result from genetic failure or ageing. Some drugs including statins, widely used by inter alia elderly, may inhibit endogenous CoQ10 synthesis. There are also chronic diseases with lower levels of CoQ10 in tissues and organs. High doses of CoQ10 may increase both circulating and intracellular levels, but there are conflicting results regarding bioavailability. Here, we review the current knowledge of CoQ10 biosynthesis and primary and acquired CoQ10 deficiency, and results from clinical trials based on CoQ10 supplementation. There are indications that supplementation positively affects mitochondrial deficiency syndrome and some of the symptoms of ageing. Cardiovascular disease and inflammation appear to be alleviated by the antioxidant effect of CoQ10. There is a need for further studies and well-designed clinical trials, with CoQ10 in a formulation of proven bioavailability, involving a greater number of participants undergoing longer treatments in order to assess the benefits of CoQ10 treatment in neurodegenerative disorders, as well as in metabolic syndrome and its complications.
... Supplementation with 5 µM CoQ is an efficient way of protecting endothelial cells in vitro against damage caused by hyperglycemia and angiotensin II [10,12]. Indeed, CoQ supplementation has substantiated clinical benefits in the prevention and treatment of hypertension and T2DM [28,40,79,81,82], and recently it has been reported that the beneficial effects of CoQ in lowering the CVD risk are associated with improving endothelial health [83]. The in vitro results presented herein regarding the effects of plasma from patients receiving Ub oral supplementation for 1 year on endothelial are limited only to the analysis of cell necrosis, and they are consistent with these data. ...
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Ubiquinol can protect endothelial cells from multiple mechanisms that cause endothelial damage and vascular dysfunction, thus contributing to dementia. A total of 69 participants diagnosed with mild cognitive impairment (MCI) received either 200 mg/day ubiquinol (Ub) or placebo for 1 year. Cognitive assessment of patients was performed at baseline and after 1 year of follow-up. Patients’ cerebral vasoreactivity was examined using transcranial Doppler sonography, and levels of Ub and lipopolysaccharide (LPS) in plasma samples were quantified. Cell viability and necrotic cell death were determined using the microvascular endothelial cell line bEnd3. Coenzyme Q10 (CoQ) levels increased in patients supplemented for 1 year with ubiquinol versus baseline and the placebo group, although higher levels were observed in male patients. The higher cCoQ concentration in male patients improved cerebral vasoreactivity CRV and reduced inflammation, although the effect of Ub supplementation on neurological improvement was negligible in this study. Furthermore, plasma from Ub-supplemented patients improved the viability of endothelial cells, although only in T2DM and hypertensive patients. This suggests that ubiquinol supplementation could be recommended to reach a concentration of 5 μg/mL in plasma in MCI patients as a complement to conventional treatment.
... Paolisso et al. [37] proposed that, supplementation with 500 mg vitamin C twice daily for 4 months reduced the plasma levels of LDL, TC, TG and insulin significantly. In another study Watts et al. [38] proposed that, administration of 800 IU/day alpha tochopherol for 6 weeks has not beneficial effect on serum glucose and HbA1c in type 2 diabetic women. Cinaz et al. [39] observed that 900 IU/day vitamin E can improve insulin due to oxidative stress reduction. ...
Article
Cardiovascular diseases (CVD) affect 1 in 3 adults and remain the leading causes of death in America. Advancing age is the major risk factor for CVD. Recent plateaus in CVD-related mortality rates in high income countries after decades of decline highlight a critical need to identify novel therapeutic targets and strategies to mitigate and manage the risk of CVD development and progression. Vascular dysfunction, characterized by endothelial dysfunction and large elastic artery stiffening, is independently associated with an increased CVD risk and incidence and is therefore an attractive target for CVD prevention and management. Vascular mitochondria have emerged as an important player in maintaining vascular homeostasis. As such, age and disease related impairments in mitochondrial function contribute to vascular dysfunction and consequent increases in CVD risk. This review outlines the role of mitochondria in vascular function and discusses the ramifications of mitochondrial dysfunction on vascular health in the setting of age and disease. The adverse vascular consequences of increased mitochondria derived reactive oxygen species, impaired mitochondrial quality control and defective mitochondrial calcium cycling are emphasized, in particular. Current evidence for both lifestyle and pharmaceutical mitochondrial-targeted strategies to improve vascular function is also presented.
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The temporal disappearance of natural antioxidants associated with human low density lipoprotein (LDL) in relation to the appearance of various classes of lipid hydroperoxides was investigated under three types of oxidizing conditions. Freshly isolated LDL from plasma of healthy subjects was free of detectable amounts of lipid hydroperoxides as measured by HPLC postcolumn chemiluminescence detection. Exposure of such LDL to a mild, constant flux of aqueous peroxyl radicals led to rapid and complete oxidation of ubiquinol-10, followed by slower partial depletion of lycopene, beta-carotene, and alpha-tocopherol. After an initial lag period of complete inhibition of detectable lipid peroxidation, formation of hydroperoxides of cholesterol esters, triglycerides, and phospholipids was observed. The onset of detectable lipid peroxidation corresponded closely with the completion of ubiquinol-10 consumption. However, small amounts of ascorbate, present as a contaminant in the LDL preparation, rather than ubiquinol-10 itself were responsible for the initial lag period. Thus, complete consumption of ubiquinol-10 was preceded by that of ascorbate, and exposure of ascorbate-free LDL to aqueous peroxyl radicals resulted in immediate formation of detectable amounts of lipid hydroperoxides. The rate of radical-mediated formation of lipid hydroperoxides in ascorbate-free LDL was low as long as ubiquinol-10 was present, but increased rapidly after its consumption, even though more than 80% and 95% of endogenous carotenoids and alpha-tocopherol, respectively, were still present. Qualitatively similar results were obtained when peroxyl radicals were generated within LDL or when the lipoprotein was exposed to oxidants produced by activated human polymorphonuclear leukocytes. LDL oxidation was reduced significantly by supplementing the lipoprotein preparation with physiological amounts of either ascorbate or ubiquinol-10. Our data show that ubiquinol-10 is much more efficient in inhibiting LDL oxidation than either lycopene, beta-carotene, or alpha-tocopherol.
Article
The atherogenic effects of low-density lipoprotein (LDL) may be mediated, in part, by its effect(s) on endothelial-derived nitric oxide (NO). To determine whether LDL can modulate NO production by changing NO synthase expression, we treated human saphenous vein endothelial cells with increasing concentrations of native or oxidized LDL (0-100 micrograms/ml) for various durations (0-72 h). Oxidized, but not native LDL caused a time-dependent decrease in steady-state NO synthase mRNA levels. This coincided with a maximal 56% decrease in NOS activity was determined by [3H]arginine to [3H]citrulline conversion. In the presence of actinomycin D, treatment with oxidized LDL reduced the half-life of NO synthase mRNA from 36 to 10 h. This decrease in NO synthase mRNA correlated with the degree of LDL oxidation and was attenuated by pretreatment with cycloheximide. Nuclear run-off studies showed a biphasic transcriptional pattern of NO synthase gene with an initial 25% decrease during the first 6 h followed by a maximal 2.2-fold increase over baseline during the subsequent 18 h. These results indicate that oxidized LDL regulates endothelial NOS expression through a combination of early transcriptional inhibition and post-transcriptional mRNA destabilization.
Article
The mechanisms for the development of vascular disease in diabetes mellitus are poorly understood. Summarized here are studies, which demonstrate that one possible mechanism lies in the fact that endothelial cell function is impaired. Endothelium-dependent relaxations of diabetic blood vessels or normal vessels exposed briefly to elevated glucose are abnormal, which suggests altered release or action of endothelium-derived nitric oxide or eicosanoids as a result of elevated glucose exposure. Aldose reductase, oxygen-derived free radicals, protein kinase C, Na+, K+-ATPase, and advanced glycosylation end products may be involved. Using pharmacological strategies, the studies summarized implicate these mechanisms and may suggest therapeutic avenues in the treatment of diabetic vascular disease.
Article
Abstract—Flow-mediated dilatation (FMD) of conduit arteries is dependent on an intact endothelium, although the mechanisms are not fully understood. Using high-resolution ultrasound, we examined the role of endothelial mediators in radial artery dilatation in response to transient (short period of reactive hyperemia) and sustained (prolonged period of reactive hyperemia, hand warming, or an incremental infusion of acetylcholine into the distal radial artery) hyperemia. After short episodes of reactive hyperemia, FMD was abolished by local infusion of the nitric oxide synthesis inhibitor N,monomethyl-L-arginine (5.361.2% versus 0.760.7%, P,0.001). In contrast, basal vessel diameter and dilatation after prolonged episodes of reactive hyperemia, hand warming, and distal infusion of acetylcholine were not attenuated by nitric oxide synthesis inhibition. Inhibition of cyclooxygenase,or local autonomic
Article
Aims Vascular endothelial dysfunction, an early marker of atherosclerosis, has been demonstrated in Type 2 diabetes mellitus (DM). Vitamin E preserves endothelial function in animal models of diabetes and reduces cardiovascular risk. We examined endothelial function and the effect of vitamin E supplements in uncomplicated Type 2 DM. Methods Forty-eight subjects with Type 2 DM and 21 controls had endothelial function assessed using forearm venous occlusion plethysmography with endothelium-independent (sodium nitroprusside) and dependent (acetylcholine, bradykinin) vasodilators. Those with diabetes received 1600 iu daily oral α-tocopherol or placebo, double-blind for 8 weeks, and had endothelial function reassessed. Results The diabetic group had higher HbA1c (6.9 ± 1.4 vs 4.8 ± 0.6%; P < 0.01) and systolic (145 ± 15 vs 130 ± 16 mmHg; P < 0.01) but not diastolic blood pressure (79 ± 8 vs 76 ± 9 mmHg; P = 0.15). There was blunted vasodilation to acetylcholine (15 μg/min; P < 0.01) in subjects with diabetes. Vasodilation to sodium nitroprusside and bradykinin was similar (all P > 0.1). α-tocopherol did not affect vasodilation to nitroprusside (P > 0.1), acetylcholine (P > 0.1) or bradykinin (P > 0.1). Conclusions There may be receptor-specific endothelial dysfunction in subjects with uncomplicated Type 2 DM. This is not improved by treatment with α-tocopherol. Diabet. Med. 16, 304–311 (1999)
Article
A fast single-step lipid extraction procedure and high-performance liquid chromatography with in-line uv and electrochemical detection are used for the simultaneous quantitative determination of tocopherols, ubiquinols, and ubiquinones in blood, plasma, tissue homogenates, and subcellular fractions. The compounds of interest can be quantitatively extracted into hexane from a sodium dodecyl sulfate-treated aqueous homogenate after precipitation of protein by addition of an equal volume of ethanol. α-, γ-, and δ-Tocopherol, ubiquinol 9, ubiquinol 10, and ubiquinones 9 and 10 can be well separated on a reversed phase column. Ubiquinones are detected at 275 nm by the uv detector, and ubiquinols and tocopherols by the electrochemical detector in the oxidative mode. Quantitation is done by comparing chromatographic peak heights to those of a standard solution containing known amounts of tocopherols, ubiquinols 9 and 10, and ubiquinones 9 and 10, analyzed under identical conditions. The high sensitivity of the electrochemical detection allows operation at low potentials (+0.5 V) with low detector response, but high selectivity for the easily oxidizable tocopherols and ubiquinols and decreased baseline noise. The uv detection limits the overall sensitivity of the procedure to 2 pmol ubiquinone, corresponding to 0.1 μm ubiquinone in the lipid extract. The ranges of values obtained for rat and guinea pig tissues, for rat liver mitochondria, and for blood and plasma from rats and humans are given.
Article
Reports from several research groups--including two small double-blind clinical studies--indicate that supplemental coenzyme Q10 (CoQ) is moderately effective as a treatment for hypertension, in humans and in animals. Its efficacy is associated with a decrease in total peripheral resistance, and appears to reflect a direct impact of CoQ on the vascular wall. A reasonable interpretation of these findings is that CoQ is acting as an antagonist of vascular superoxide--either scavenging it, or suppressing its synthesis. By improving the efficiency of shuttle mechanisms that transfer high-energy electrons from the cytoplasm to the mitochondrial respiratory chain, CoQ may decrease cytoplasmic NADH levels and thereby diminish the reductive power that drives superoxide synthesis in endothelium and vascular smooth muscle. If CoQ therapy does indeed lower vascular superoxide levels, it can be expected to decrease the atherothrombotic risk associated with hypertension, and may have broader utility in the management of disorders characterized by endotheliopathy.
Article
Non-insulin-dependent diabetes mellitus (NIDDM) results from an imbalance between insulin sensitivity and insulin secretion. Both longitudinal and cross-sectional studies have demonstrated that the earliest detectable abnormality in NIDDM is an impairment in the body's ability to respond to insulin. Because the pancreas is able to appropriately augment its secretion of insulin to offset the insulin resistance, glucose tolerance remains normal. With time, however, the beta-cell fails to maintain its high rate of insulin secretion and the relative insulinopenia (i.e., relative to the degree of insulin resistance) leads to the development of impaired glucose tolerance and eventually overt diabetes mellitus. The cause of pancreatic "exhaustion" remains unknown but may be related to the effect of glucose toxicity in a genetically predisposed beta-cell. Information concerning the loss of first-phase insulin secretion, altered pulsatility of insulin release, and enhanced proinsulin-insulin secretory ratio is discussed as it pertains to altered beta-cell function in NIDDM. Insulin resistance in NIDDM involves both hepatic and peripheral, muscle, tissues. In the postabsorptive state hepatic glucose output is normal or increased, despite the presence of fasting hyperinsulinemia, whereas the efficiency of tissue glucose uptake is reduced. In response to both endogenously secreted or exogenously administered insulin, hepatic glucose production fails to suppress normally and muscle glucose uptake is diminished. The accelerated rate of hepatic glucose output is due entirely to augmented gluconeogenesis. In muscle many cellular defects in insulin action have been described including impaired insulin-receptor tyrosine kinase activity, diminished glucose transport, and reduced glycogen synthase and pyruvate dehydrogenase. The abnormalities account for disturbances in the two major intracellular pathways of glucose disposal, glycogen synthesis, and glucose oxidation. In the earliest stages of NIDDM, the major defect involves the inability of insulin to promote glucose uptake and storage as glycogen. Other potential mechanisms that have been put forward to explain the insulin resistance, include increased lipid oxidation, altered skeletal muscle capillary density/fiber type/blood flow, impaired insulin transport across the vascular endothelium, increased amylin, calcitonin gene-related peptide levels, and glucose toxicity.
Article
Published experimental data pertaining to the participation of coenzyme Q as a site of free radical formation in the mitochondrial electron transfer chain and the conditions required for free radical production have been reviewed critically. The evidence suggests that a component from each of the mitochondrial NADH-coenzyme Q, succinate-coenzyme Q, and coenzyme QH2-cytochrome c reductases (complexes I, II, and III), most likely a nonheme iron-sulfur protein of each complex, is involved in free radical formation. Although the semiquinone form of coenzyme Q may be formed during electron transport, its unpaired electron most likely serves to aid in the dismutation of superoxide radicals instead of participating in free radical formation. Results of studies with electron transfer chain inhibitors make the conclusion dubious that coenzyme Q is a major free radical generator under normal physiological conditions but may be involved in superoxide radical formation during ischemia and subsequent reperfusion. Experiments at various levels of organization including subcellular systems, intact animals, and human subjects in the clinical setting, support the view that coenzyme Q, mainly in its reduced state, may act as an antioxidant protecting a number of cellular membranes from free radical damage.