(Circulation. 1996;93:1346-1353.)
© 1996 American Heart Association, Inc.
Articles |
Cigarette Smoking Potentiates Endothelial Dysfunction of Forearm Resistance Vessels in Patients With Hypercholesterolemia
Role of Oxidized LDL
From Medizinische Klinik III (T.H., S.K., T.M., H.J., H.D.) and Medizinische Biometrie und Statistik (M.O.), Universität Freiburg, Germany, and A.I. Virtanen Institute and Department of Medicine, University of Kuopio (S.Y.-H., J.L.), Finland.
Correspondence to Helmut Drexler, MD, Medizinische Klinik III, Hugstetterstr 55, 79106 Freiburg, Germany.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background Risk factors for atherosclerosis such as hypercholesterolemia and hypertension are associated with endothelial dysfunction of conduit and resistance vessels; however, the interaction of these risk factors and underlying mechanisms affecting endothelial function remain to be determined. The present study investigated the role of long-term smoking and hypercholesterolemia and their impact on endothelial function of peripheral resistance vessels in relation to plasma levels of autoantibodies against oxidized LDL, which has been implicated in the development of endothelial dysfunction and atherosclerosis.
Methods and Results The vascular responses to the endothelium-dependent agent acetylcholine (7.5, 15, 30, and 60 µg/min) and the endothelium-independent agent sodium nitroprusside (1, 3, and 10 µg/min) were studied in normal control subjects (n=10), patients with hypercholesterolemia (n=15), long-term smokers (n=15), and hypercholesterolemic patients who smoked (n=15). Drugs were infused into the brachial artery, and forearm blood flow (FBF) was measured by venous occlusion plethysmography. The FBF responses to acetylcholine were significantly blunted in all three patient groups compared with normal control subjects (P<.05). The acetylcholine-induced increase in FBF was significantly attenuated in patients with hypercholesterolemia who smoked compared with hypercholesterolemic nonsmokers and normocholesterolemic smokers (P<.05 for both). The response to sodium nitroprusside was not statistically different in all four groups. Plasma levels of autoantibody titer against oxidized LDL were inversely related to acetylcholine-induced changes in FBF (r=-.53, P<.002) and were substantially increased in the group with both risk factors.
Conclusions These results demonstrate that cigarette smoking and hypercholesterolemia synergistically impair endothelial function and that their combined presence is associated with increased plasma levels of autoantibodies against oxidized LDL. These observations raise the possibility that long-term smoking potentiates endothelial dysfunction in hypercholesterolemic patients by enhancing the oxidation of LDL.
Key Words: hypercholesterolemia • endothelium • lipoproteins • smoking
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The vascular endothelium plays a key role in the local regulation of vascular tone by the release of vasodilator substances (ie, EDRF and prostacyclin) and vasoconstrictor substances (ie, thromboxane A2, free radicals, and endothelin).1 Previous studies revealed the importance of EDRF in both basal and stimulated control of vascular tone in large conduit vessels and resistance vessels. Evidence exists that the regulatory function of the endothelium is altered in numerous cardiovascular disorders such as hypercholesterolemia2 3 and hypertension.4 Cigarette smoking is another important risk factor for the development of atherosclerosis and is strongly associated with coronary, cerebral, and peripheral vascular disease.5 6 The exact mechanism of smoking-related arterial damage is not known. A reduction in prostacyclin production and an enhanced platelet–vessel wall interaction was described.7 8 Less information is available regarding the effects of smoking on endothelial control mechanisms of vascular tone. There is controversy about smoking as an independent predictor of abnormal vasomotor function in the coronary9 10 11 and peripheral12 13 14 circulation; although recent studies reported impaired flow-mediated vasodilation of brachial artery in clinically healthy smokers,12 stimulated endothelium-dependent relaxation of peripheral resistance vessels was found to be unaffected.13 14
Importantly, the underlying mechanisms involved in the pathophysiology of endothelial dysfunction in hypercholesterolemia or long-term smoking are not clearly identified. Several mechanisms such as reduced synthesis and release of EDRF15 16 or enhanced inactivation of EDRF after its release from endothelial cells by radicals or oxidized LDL have been postulated.17 18 Previous studies have noted increased plasma levels of autoantibodies against oxidized LDL and increased circulating products of lipid peroxidation in long-term smokers,19 20 raising the possibility that long-term smoking potentiates endothelial dysfunction in hypercholesterolemia by increasing circulating and tissue levels of oxidized LDL. Accordingly, the present study was designed to examine the effect of smoking on endothelium-dependent relaxation in patients with and without hypercholesterolemia and to assess the relationship of endothelial function and plasma level of autoantibodies against oxidized LDL.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Subjects
A total of 55 subjects were examined: 15 patients with hypercholesterolemia, 15 long-term smokers, 15 hypercholesterolemic patients who smoked, and 10 normal subjects. Subjects with hypercholesterolemia were admitted into the study if their serum LDL cholesterol levels, measured after a 12-hour fasting period, were greater than the 75th percentile for age and sex. Long-term smokers were included if they had a history of >20 pack-years (1 pack-year defined as smoking 20 cigarettes per day for 1 year or the equivalent). Each subject was screened by clinical history, physical examination, and routine chemical analyses to exclude those with hematological, renal, or hepatic dysfunction. No patient had diabetes mellitus, arterial hypertension, congestive heart failure, or any other systemic disease predisposing them to vasculitis or Raynaud's phenomenon; in particular, none of the control group had any evidence of cardiac disease, hyperlipidemia, or any other systemic condition. Table 1
lists the characteristics of the four
study groups. All participants gave written informed consent, and the
study protocol was approved by the Ethical Committee of the University
of Freiburg.
|
Protocol
All studies were performed in the early afternoon in a 23°C
temperature-controlled room with patients in the postabsorptive
state. Participants were asked to refrain from drinking alcohol and
smoking cigarettes within 12 hours of their study. Under local
anesthesia and sterile conditions, a 20-gauge polyethylene
catheter was inserted into the brachial artery of the nondominant arm
(usually the left) for drug infusion. This arm was slightly elevated
above the level of the right atrium, and a mercury-filled Silastic
strain gauge was placed on the widest part of the forearm. The strain
gauge was connected to an electronically calibrated plethysmograph. A
wrist cuff was inflated to suprasystolic pressures 1 minute
before and during each measurement to exclude hand circulation. A cuff
placed on the upper arm was inflated to 40 mm Hg to occlude venous
outflow from the extremity. Flow measurements were recorded for 5
seconds every 10 seconds and expressed as milliliters per minute per
100 mL tissue; the mean flow value of seven consecutive readings was
used for analyses. Systolic, diastolic, and
mean arterial pressures and heart rate were determined at
the contralateral arm with a Dinamap (845 oscillometric) blood pressure
recorder. FVR was calculated as the ratio of mean blood pressure to
FBF and expressed as units reflecting millimeters of mercury per
milliliter per minute per 100 mL tissue.
All subjects rested at least 30 minutes after catheter placement to establish a stable baseline. Basal measurements were then obtained during intra-arterial infusion of 0.9% saline at a rate of 1.66 mL/min. To assess endothelium-dependent vasodilation, acetylcholine chloride (100 mg/10 mL, Dispersa) was administered at increasing dosages of 7.5, 15, 30, and 60 µg/min. To evaluate vascular smooth muscle relaxation, each study participant received an intra-arterial infusion of sodium nitroprusside. This agent was given at doses of 1, 3, and 10 µg/min. Each dose was infused at a rate of 1.66 mL/min for 5 minutes, and FBF was measured during the last 2 minutes of each infusion. A 30-minute rest period was allowed, and basal measurements were repeated between the infusion of the two drugs. The sequence of administration of both drugs was randomized to avoid any bias related to the order of drug infusion.
After another 30-minute rest period, the nonselective postjunctional
-adrenergic receptor antagonist phentolamine
was infused at a constant rate of 12
µg·min-1·100
mL-1 forearm volume in five smokers and
five control subjects. At these doses, phentolamine produces
effective and complete -adrenergic blockade.21
After another basal measurement was taken, a cumulative
dose-response curve to acetylcholine with the same doses during
simultaneous infusion of phentolamine was
obtained.
Measurement of Autoantibodies Against Oxidized LDL
In a subset of patients, blood samples were obtained after a
12-hour fasting period on the same day as the flow measurements. Serum
was separated from blood elements by centrifugation,
and aliquots were stored at -20°C. Autoantibodies against
oxidized LDL were measured according to a modification of previously
published methods.20 For each set of samples, three
identical 96-well microtitre plates (NUNC Immunoplate) were used: one
plate was coated with native LDL, a second plate with LDL oxidized with
copper for 24 hours, and a third plate with postcoat only (see below).
Plates were coated with 50 µL antigen (5 µg/mL) per well in PBS
overnight at 4°C. To prevent oxidation of native LDL, PBS contained
0.27 mmol/L EDTA and 20 µmol/L BHT. Each well was washed three times
with PBS containing 0.05% Tween 20 and once with water. Plates were
blocked with 2% BSA (Sigma Chemical Co) in PBS containing 0.27 mmol/L
EDTA and 20 µmol/L BHT for 2 hours at 4°C. Samples (50 µL per
well) were pipetted on the plates at 1:20, 1:50, and 1:100 dilutions;
plates were incubated overnight and washed as above.
Affinity-purifiedanti-human IgG (1 mg/mL, 1:5000 dilution;
Zymed Laboratories) conjugated with horseradish peroxidase was added to
the wells in PBS containing 1% BSA, 0.05% Tween 29, 0.27 mmol/L EDTA,
and 20 µmol/L BHT, and the plates were incubated at 4°C for 4
hours. Wells were then washed as above and incubated with
o-phenylene-diamine (Fluka) for 5 minutes. Absorbances
were measured at 492 nm with a microplate reader (Multiscan NVV/340).
All measurements were done in duplicate (J.L. and S.Y.-H.) without
knowledge of the FBF measurements. Postcoat values for each dilution
were subtracted from the analyzed samples. Results were
expressed as absorbance units and as a ratio of oxidized LDL to native
LDL at each dilution. Absorbance results obtained with 1:20 dilution
are reported.
Statistical Analysis
Descriptive statistics are expressed as mean±SEM. The influence
of smoking status and hypercholesterolemia on
the responses to acetylcholine and sodium nitroprusside and on the
plasma levels of autoantibodies against oxidized LDL was assessed in a
two-by-two factorial design and analyzed by two-way
ANOVA for repeated measures considering interactions. Additionally, the
four groups were compared by one-way ANOVA for repeated measures
followed by Tukey's Studentized Range Test. The impact of plasma
levels of autoantibodies against oxidized LDL on the maximal
acetylcholine-induced blood flow response was analyzed by
univariate and multiple regression analysis. All
values of P<.05 were considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Patient Characteristics
The baseline characteristics of the normal subjects and the patients with hypercholesterolemia and/or a history of smoking were similar, except for the lipid profile and smoking status. By selection, there were no smokers in the control and hypercholesterolemic groups. The cigarette consumption with a self-reported pack-year history was similar in both smoking groups. As defined by enrollment criteria, plasma LDL cholesterol and total cholesterol levels were significantly higher in the two hypercholesterolemic groups than in the control and smoking groups. There were no significant differences in the HDL cholesterol and triglyceride levels between groups. Table 1
gives the different lipoprotein fractions that were
measured subsequently. The mean arterial blood pressure,
basal FBF, and resting FVR of each group were similar.
Vascular Response to Acetylcholine
In normal subjects, stepwise-increasing dosages of
acetylcholine augmented FBF from 2.9±0.3 to 21.2±0.8
mL·min-1·100
mL-1 forearm tissue. The vasodilator
response to all four acetylcholine dosages was significantly less in
the other three groups compared with normal subjects
(P<.05; Fig 1, top). Furthermore, there was
a difference between the group with
hypercholesterolemia and smoking compared with
the group with hypercholesterolemia alone and
the group with smoking alone: the increase in FBF was blunted in the
group with both risk factors, achieving statistical significance at the
30-µg/min dose (6.1±0.7 versus 10.3±0.8 and 9.2±0.9
mL·min-1 · 100
mL-1 tissue, respectively;
P<.05) and the 60-µg/min dose (7.8±1.1 versus 14.3±1.3
and 12.5±1.2 mL·min-1 · 100
mL-1 tissue, respectively;
P<.05). Two-way ANOVA showed that the effect of smoking
status was highly significant (P=.0001). A similar result
was obtained for hypercholesterolemia
(P=.0009).
|
P<.05 vs all other groups. Data
are mean±SEM.
Because there was no change in blood pressure, the change in FBF during
acetylcholine infusion reflected changes in FVR. FVR decreased from
38.1±4.4 to 4.5±0.3 U in the control group and from 39.2±4.9 to
14.9±2.0 U in the group with both risk factors. (Fig 1, bottom). These
smoking hypercholesterolemic patients had
significantly less vasorelaxation than the other three groups at the
15-, 30-, and 60-µg/min dose (P<.05).
To exclude an effect of sex on the results, the statistical
analysis was performed for men only (Table 2).
There was no difference in statistical significance between the
analysis for men only and the analysis including
women.
|
Vascular Response to Sodium Nitroprusside
To determine whether smoking and
hypercholesterolemia affect smooth muscle
function directly, the vasodilator response to sodium nitroprusside was
examined. Intra-arterial infusion of sodium
nitroprusside did not change mean blood pressure or heart rate in
either group. There was a dose-dependent increase in FBF in all
four groups (Fig 2, top). The maximal response was
14.7±0.7 mL·min-1·100
mL-1 in normal subjects, 14.1±0.7
mL·min-1·100
mL-1 in patients with
hypercholesterolemia, 13.9±0.9
mL·min-1·100
mL-1 in long-term smokers, and
13.1±1.0 mL·min-1·100
mL-1 in the group with both risk
factors (P=NS). Accordingly, changes in FVR induced by
sodium nitroprusside were similar in all four groups (Fig 2,
bottom).
|
Relation Between Autoantibodies Against Oxidized LDL and
Endothelium-Dependent Vasodilation
In normal subjects, the autoantibody titers against oxidized LDL
averaged 0.10±0.02 (arbitrary units). There was no significant
difference between control subjects and smokers (0.13±0.03) and
patients with hypercholesterolemia (0.15±0.03)
as assessed by one-way ANOVA. However, if a two-by-two
factorial analysis is used (taking into account all smokers and
all hypercholesterolemic patients), both smoking
(P<.05) and hypercholesterolemia
(P<.01) were significant factors for plasma level of
autoantibodies against oxidized LDL. Patients with both risk factors
showed a marked increase (0.26±0.04, P<.05 by ANOVA; Fig 3). There was a significant relation between
autoantibody titers against oxidized LDL and maximal FBF response to
acetylcholine (Fig 4) and, to a lesser degree, between
the LDL-to-HDL ratio and the maximal acetylcholine blood flow response
(r=-.36, P<.05). In contrast, no
relationship between LDL or HDL and the blood flow responses to
acetylcholine was noted. By use of several lipid fractions (LDL, HDL,
triglycerides, LDL-to-HDL ratio, and oxidized LDL) in a
multivariate analysis, autoantibody titers
against oxidized LDL were the only independent factors related to
endothelial dysfunction (P<.005).
|
|
Effect of -Adrenergic Blockade
To exclude a heightened sympathetic tone as contributing factor of
vascular response in smokers, the acetylcholine-induced changes in
blood flow were determined in five normal control subjects and five
long-term smokers before and after -adrenoceptor blockade
with phentolamine. The infusion of phentolamine caused
significant vasodilation in both groups; the response was significantly
smaller in long-term smokers compared with control subjects
(increase from 2.7±0.2 to 4.5±0.3
mL·min-1·100
mL-1 in smokers versus an increase from
3.1±0.2 to 6.4±0.3
mL·min-1·100
mL-1). During simultaneous
infusion of phentolamine and increasing dosages of
acetylcholine, FBF increased from 4.5 to 14.6
mL·min-1·100
mL-1 in long-term smokers and from
6.6 to 24.6 mL·min-1·100
mL-1 in normal control subjects. Thus,
the acetylcholine-induced increase in blood flow was augmented to a
similar extent by -adrenergic blockade in normal control
subjects and long-term smokers (Fig 5).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
This study demonstrates impaired endothelium-dependent vasodilation of forearm resistance vessels in long-term smokers and hypercholesterolemic patients and, importantly, a synergistic adverse effect of smoking and hypercholesterolemia associated with an increased autoantibody titer against oxidized LDL. These observations raise the possibility that long-term smoking potentiates endothelial dysfunction in hypercholesterolemic patients by enhancing the oxidation of LDL.
Although smoking represents an important risk factor for atherosclerosis, the pathogenesis of smoking-related vascular disease remains to be fully determined. Vita et al9 found no significant association between smoking and endothelial dysfunction of epicardial arteries, whereas others reported abnormal coronary vasodilation in response to acetylcholine10 and increased flow.22 Furthermore, preliminary data indicate a reduced coronary flow reserve in long-term cigarette smokers, pointing to a resistance vessel abnormality that may predispose to myocardial ischemia.11 The effect of smoking on endothelial function of large conduit vessels of the human forearm was examined by Celermajer et al,12 who found an impaired brachial artery dilation in response to increased flow. The present study extends these previous observations by demonstrating that long-term smoking is associated with markedly reduced acetylcholine responses in forearm resistance vessels. This impairment seems to be restricted to endothelium-mediated dilation because the effects of the endothelium-independent vasodilator sodium nitroprusside were not attenuated. Whether smoking causes endothelial dysfunction in resistance vessels appears to depend on the degree of cigarette consumption. Rangemark and Wennmalm13 demonstrated in young smokers an enhanced vascular response to acetylcholine, sodium nitroprusside, and reactive hyperemia, suggesting a smoking-induced nonspecific enhancement of sensitivity of forearm resistance vessels to all tested vasodilator stimuli. Furthermore, Jacobs et al14 showed no significant differences in FBF in response to methacholine in young smokers compared with healthy control subjects. In these particular studies, however, the patient population was younger and the degree of cigarette consumption was considerably less than in the present study. A dose dependence of smoking-related endothelial dysfunction also is supported by recent studies showing a significant inverse correlation between pack-years smoked and flow-mediated dilation of the brachial artery.12 Previous work established that the vasodilator response to acetylcholine in humans is in part related to the release of NO.23 Thus, the demonstration of an impaired acetylcholine response in smokers is consistent with the notion that smoking is associated with impaired stimulated release (or availability) of NO from peripheral resistance vessels. Recent data from Kiowski and colleagues24 complement our findings by demonstrating that the vasoconstrictor response to inhibition of NO by L-NMMA is reduced in long-term smokers, implicating impaired basal NO-mediated vasodilation.
Short-term smoking results in a variety of
cardiovascular changes, including increased heart rate
and blood pressure, cutaneous vasoconstriction, and increased muscle
blood flow.25 Furthermore, cardiovascular
and metabolic effects induced by short-term smoking are
prevented by combined - and ß-adrenergic blockade, indicating
that these effects are mediated at least in part by an activation of
the sympathetic nervous system.26 27 28 29 To determine whether
an increased adrenergic vasoconstriction is involved in the diminished
vascular vasodilation in response to acetylcholine, we assessed the
effect of -adrenergic inhibition on basal and stimulated flow
(acetylcholine) in control subjects compared with long-term
smokers. The increase in blood flow in response to phentolamine
was significantly less in smokers, indicating less -adrenergic
influences on basal blood flow. The acetylcholine-induced changes
in FBF in the presence of phentolamine were comparable in both
groups. This observation indicates that a heightened sympathetic tone
is not responsible for the blunted
endothelium-dependent vasodilation.
Our findings of impaired vasodilation of forearm resistance vessels in hypercholesterolemic subjects in response to acetylcholine but not to the endothelium-independent drug sodium nitroprusside are in agreement with the results of recent investigations.2 3 The present study focused on the impact of long-term smoking on endothelial dysfunction in patients with hypercholesterolemia. We found a synergistic adverse effect of smoking and hypercholesterolemia on endothelial function of the human forearm microcirculation. Endothelium-dependent responses in patients were substantially impaired in patients with both risk factors compared with long-term smokers or hypercholesterolemic subjects. Similarly, synergistic adverse effects of smoking and hypercholesterolemia on the vasculature have been demonstrated in cholesterol-fed rabbits; ie, brief periods of sidestream smoking accelerated atherosclerotic plaque development.30 Moreover, inhalation of sidestream cigarette smoking markedly accelerated development of arteriosclerotic plaques in cockerels.31 The mechanism of smoking-associated endothelial dysfunction is not established. Some studies have demonstrated a direct toxic effect of tobacco smoking on human endothelium.32 33 Cigarette smoking may also predispose to the development of atherosclerosis through its effects on hemostasis. In smokers, fibrinogen levels generally are higher,34 platelet reactivity is enhanced,35 and thrombin generation is increased,36 all of which may compromise endothelial function.
Importantly, both hypercholesterolemia and smoking have been shown to cause endothelial dysfunction through formation of superoxide anions in experimental models.37 38 Indeed, several studies have suggested that the deleterious effects of smoking are mediated by increased oxidative stress. Smokers have decreased levels of vitamins with antioxidant properties such as vitamins E and C and beta carotene.39 40 Free radicals generated by smoking may accelerate lipid peroxidation and thereby increase the formation of oxidized LDL, known to be a potent inhibitor of endothelium-dependent vasodilation in experimental studies.41 Indeed, there is evidence that circulating products of lipid peroxidation are increased in smokers,19 possibly related to exposure to oxidative stress.42 As discussed previously, oxidative modification of LDL is thought to be a key process in the development of endothelial dysfunction41 and atherosclerosis.43 In the present study, autoantibodies against oxidized LDL were measured with LDL oxidized with copper for 24 hours as the antigen. In some recent studies, malondialdehyde LDL has been used as the antigen in similar assays. Malondialdehyde lysine epitopes present in malondialdehyde LDL represent one class of oxidation-derived epitopes generated in oxidized LDL, but there are many others such as hydroxynonenal epitopes and other peroxidation-derived aldehyde adducts.43 Oxidized LDL was chosen because it contains a collection of various epitopes typical for the oxidation process and thus may mimic the situation in the arterial wall better than malondialdehyde LDL or hydroxynonenal LDL. However, the density of each of the oxidation-derived epitopes in oxidized LDL is likely to be much lower than in malondialdehyde LDL and hydroxynonenal LDL, which rely on only one or a few epitopes generated during the reaction with aldehydes. Consequently, assays with oxidized LDL as the antigen may be less sensitive than assays with malondialdehyde LDL or hydroxynonenal LDL but should reflect a more generalized, time-averaged immune response against oxidized LDL (ie, comparable to hemoglobin A1c reflecting average plasma glucose over a period of time); therefore, our approach may have advantages over direct measurements of altered epitopes. Of note, the oxidative modification of LDL occurs mainly in the vascular wall because of the presence of antioxidants in the plasma. To assess the role of lipid oxidation in humans, previous studies have investigated the ability of LDL (isolated from plasma) to oxidize in vitro by determination of lag phases for formation of conjugated dienes.44 While these measurements were confined to the state and properties of circulating LDL, autoantibodies against oxidized LDL may reflect the immune response to both plasma and vascular levels of oxidized LDL.
In the present study, moderately increased levels of autoantibody titers to oxidized LDL were noted in smokers or hypercholesterolemic patients (statistically significant in the two-by-two factorial analysis). The close relationship between plasma levels of autoantibody titers to oxidized LDL and acetylcholine-induced blood flow responses is consistent with the notion that oxidized LDL is involved in the development of endothelial dysfunction. This contention is supported by multiple regression analysis of several lipid fractions in which only autoantibodies against oxidized LDL emerged as an independent predictor of endothelial dysfunction.
In the present study, the autoantibody titers to oxidized LDL were increased markedly when both risk factors are present; these patients showed the most dramatic attenuation of endothelium-dependent vasodilation. Increased circulating autoantibodies against oxidized LDL may reflect enhanced free radical load under these circumstances that exceeds the antioxidant defense capacity, which, in turn, can profoundly impair the NO-mediated vasodilation, eg, in response to endothelium-dependent vasodilators such as acetylcholine. In this respect, it is noteworthy that increased plasma levels of autoantibody titers to oxidized LDL have been demonstrated to be highly predictive of the subsequent progression of atherosclerosis,45 implicating a potential role for oxidative stress in mediating the progression of atherosclerosis. The present study suggests that oxidized LDL may be involved in the development of endothelial dysfunction in humans, which in turn may predispose to accelerated development of atherosclerosis.
|
Selected Abbreviations and Acronyms |
|---|
|
Received July 26, 1995; revision received November 8, 1995; accepted November 20, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
-
Vane JR, Änggard EE, Botting RM.
Regulatory functions of the vascular
endothelium. N Engl J Med. 1990;323:27-36. [Medline]
[Order article via Infotrieve]
-
Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ,
Coleman SM, Loscalzo J, Dzau VJ. Impaired vasodilation of
forearm resistance vessels in hypercholesterolemic
humans. J Clin Invest. 1990;86:228-234.
-
Drexler H, Zeiher AM, Meinzer K, Just H.
Correction of endothelial dysfunction in
coronary microcirculation of
hypercholesterolaemic patients by
L-arginine. Lancet. 1991;338:1546-1550. [Medline]
[Order article via Infotrieve]
-
Panza JA, Quyyumi AA, Brush JE, Epstein SI.
Abnormal endothelium-dependent vascular relaxation
in patients with essential hypertension. N Engl
J Med. 1990;323:22-27. [Abstract]
-
Sackett DL, Gibson RW, Bross IDJ, Pickren JW.
Relation between aortic atherosclerosis and the use of
cigarettes and alcohol: an autopsy study. N
Engl J Med. 1968;279:1413-1420.
-
Kannel WB. Update on the role of cigarette
smoking in coronary artery disease. Am Heart
J. 1981;101:319-328. [Medline]
[Order article via Infotrieve]
-
Nowak J, Murray JJ, Oates JA, FitzGerald GA.
Biochemical evidence of a chronic abnormality in platelet and
vascular function in healthy individuals who smoke cigarettes.
Circulation. 1987;76:6-14.
[Abstract/Free Full Text]
-
Nadler JL, Velasco JS, Horton R. Cigarette
smoking inhibits prostacyclin formation. Lancet. 1983;1:1248-1250. [Medline]
[Order article via Infotrieve]
-
Vita JA, Treasure CB, Nabel EG, McLenachan JM, Fish
RD, Yeung AC, Vekshtein VI, Selwyn AP, Ganz P. Coronary
vasomotor response to acetylcholine relates to risk factors for
coronary artery disease.
Circulation. 1990;81:491-497.
[Abstract/Free Full Text]
-
Nitenberg A, Antony I, Foult J-M.
Acetylcholine-induced coronary vasoconstriction in young,
heavy smokers with normal coronary arteriographic
findings. Am J Med. 1993;95:71-77. [Medline]
[Order article via Infotrieve]
-
Minor RL, Oskarsson H, Rossen JD, Winniford MD.
Is coronary flow reserve reduced in chronic cigarette
smokers? Circulation. 1992;86(suppl
I):I-117. Abstract.
-
Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C,
Thomas O, Robinson J, Deanfield JE. Cigarette smoking is
associated with dose-related and potentially reversible impairment
of endothelium-dependent dilation in healthy young
adults. Circulation. 1993;88:2149-2155.
[Abstract/Free Full Text]
-
Rangemark C, Wennmalm A.
Endothelium-dependent and -independent vasodilation
and reactive hyperemia in healthy smokers.
J Cardiovasc Pharmacol. 1992;20(suppl
12):S198-S201.
-
Jacobs M-C, Lenders JWM, Kapma JA, Smits P, Thien
T. Effect of chronic smoking on
endothelium-dependent vascular relaxation in
humans. Clin Sci (Colch). 1993;85:51-55.[Medline]
[Order article via Infotrieve]
-
Cohen RA, Zitnay KM, Haudenschild CC, Cunningham
LD. Loss of selective endothelial cell
vasoactive functions caused by
hypercholesterolemia in pig coronary
arteries. Circ Res. 1988;63:903-910.
[Abstract/Free Full Text]
-
Verbeuren TJ, Jordaens FH, Zonnekeyn LL, Van Hove CE,
Coene MC, Herman AG. Effect of
hypercholesterolemia on vascular reactivity in
the rabbit. Circ Res. 1986;58:552-564.
[Abstract/Free Full Text]
-
Galle J, Mülsch A, Busse R, Bassenge E.
Effects of native and oxidized low density lipoproteins on formation
and inactivation of EDRF. Arterioscler
Thromb. 1991;11:198-203.
[Abstract/Free Full Text]
-
Minor RL Jr, Myers PR, Guerra R, Bates JN, Harrison
DG. Diet-induced atherosclerosis increases
the release of nitrogen oxides from rabbit aorta. J
Clin Invest. 1990;86:2109-2116.
-
Morrow JD, Frei B, Longmire AW, Gaziano JM, Lynch SM,
Shyr Y, Strauss WE, Oates JA, Roberts LJ. Increase in
circulating products of lipid peroxidation
(F2-isoprostanes) in smokers: smoking as a cause of
oxidative damage. N Engl J Med. 1995;332:1198-1203.
[Abstract/Free Full Text]
-
Salonen JT, Ylä-Herttuala S, Yamamoto R, Butler
S, Korpela H, Salonen R, Nyyssönen K, Palinski W, Witztum
JL. Autoantibody against oxidised LDL and progression of carotid
atherosclerosis. Lancet. 1992;339:883-887. [Medline]
[Order article via Infotrieve]
-
Kiowski W, Böhler FR, van Brummelen P, Amann
FW. Plasma noradrenaline concentration and
alpha-adrenoceptor-mediated vasoconstriction in normotensive
and hypertensive man. Clin Sci (Colch). 1981;60:483-489. [Medline]
[Order article via Infotrieve]
-
Zeiher AM, Schächinger V, Minners J.
Long-term smoking impairs endothelium-dependent
coronary arterial vasodilator function.
Circulation. 1995;92:1094-1100.
[Abstract/Free Full Text]
-
Vallance P, Collier J, Moncada S. Effects of
endothelium-derived nitric oxide on
peripheral arteriolar tone in man.
Lancet. 1989;2:997-1000. [Medline]
[Order article via Infotrieve]
-
Kiowski W, Linder L, Stoschitzky K, Pfisterer M,
Burckhardt D, Burkart F, Bühler FR. Diminished vascular
response to inhibition of endothelium-derived
nitric oxide and enhanced vasoconstriction to exogenously administered
endothelin-1 in clinically healthy smokers.
Circulation. 1994;90:27-34.
[Abstract/Free Full Text]
-
Benowitz NL. Pharmacologic aspects of cigarette
smoking and nicotine addiction. N Engl J
Med. 1988;319:1318-1330. [Medline]
[Order article via Infotrieve]
-
Cryer PE, Haymond MW, Santiago JV, Shah SD.
Norepinephrine and epinephrine release and
adrenergic mediation of smoking-associated
hemodynamic and metabolic events.
N Engl J Med. 1976;295:573-577. [Abstract]
-
Winniford MD, Wheelan KR, Kremers MS, Ugolini V, van
den Berg E, Niggemann EH, Jansen DE, Hillis LD.
Smoking-induced coronary vasoconstriction in patients with
atherosclerotic coronary artery disease: evidence for
adrenergically mediated alterations in coronary artery
tone. Circulation. 1986;73:662-667.
[Abstract/Free Full Text]
-
Quillen JE, Rossen JD, Oskarsson HJ, Minor RL, Lopez
JAG, Winniford MD. Acute effect of cigarette smoking on the
coronary circulation: constriction of epicardial and resistance
vessels. J Am Coll Cardiol. 1993;22:642-647. [Abstract]
-
Minor RL, Oskarsson H, Quillen JE, Rossen JD, Winniford
MD. Intracoronary phentolamine reverses
cigarette smoking-induced vasoconstriction of coronary
resistance vessels in humans. Circulation.
1992;86(suppl I):I-854. Abstract.
-
Penn A, Snyder CA. Inhalation of sidestream
cigarette smoke accelerates development of
arteriosclerotic plaques.
Circulation. 1993;88:1820-1825.
[Abstract/Free Full Text]
-
Zhu B-Q, Sun Y-P, Sievers RE, Isenberg WM, Glantz SA,
Parmley WW. Passive smoking increases
atherosclerosis in cholesterol-fed
rabbits. J Am Coll Cardiol. 1993;21:225-232. [Abstract]
-
Asmussen I, Kjeldsen K. Intimal ultrastructure
of human umbilical arteries: observations on arteries from newborn
children of smoking and nonsmoking mothers.
Circ Res. 1975;36:579-589.
[Abstract/Free Full Text]
-
Davis JW, Shelton L, Eigenberg DA, Hignite CE, Watanabe
IS. Effects of tobacco and non-tobacco cigarette smoking on
endothelium and platelets. Clin
Pharmacol Ther. 1985;37:529-533. [Medline]
[Order article via Infotrieve]
-
Kannel WB, D'Agostino RB, Belanger AJ.
Fibrinogen, cigarette smoking, and risk of
cardiovascular disease: insights from the Framingham
study. Am Heart J. 1987;113:1006-1010. [Medline]
[Order article via Infotrieve]
-
Wennmalm A, Benthin G, Granström EF, Persson L,
Petersson A-S, Winell S. Relation between tobacco use and
urinary excretion of thromboxane A2 and
prostacyclin metabolites in young men.
Circulation. 1991;83:1698-1704.
[Abstract/Free Full Text]
-
Kimura S, Nishinaga M, Ozawa T, Shimada K.
Thrombin generation as an acute effect of cigarette smoking.
Am Heart J. 1994;128:7-11. [Medline]
[Order article via Infotrieve]
-
Murohara T, Kygiyama K, Ohgushi M, Sugiyama S, Yasue
H. Cigarette smoke extract contracts isolated coronary
porcine arteries by superoxide anion-mediated degradation of
EDRF. Am J Physiol. 1994;266:H874-H880.
[Abstract/Free Full Text]
-
Ohara Y, Peterson TE, Harrison DG.
Hypercholesterolemia increases
endothelial superoxide anion
production. J Clin Invest. 1993;91:2546-2551.
-
Chow CK, Thacker RR, Changchit C, Bridges RB, Rehm SR,
Humble J, Turbek J. Lower levels of vitamin C and carotenes in
plasma of cigarette smokers. J Am Coll
Nutr. 1986;5:305-312. [Abstract]
-
Duthie GG, Wahle KJ. Smoking, antioxidants,
essential fatty acids and coronary heart disease.
Biochem Soc Trans. 1990;18:1051-1054. [Medline]
[Order article via Infotrieve]
-
Flavahan NA. Atherosclerosis or
liprotein-induced endothelial dysfunction:
potential mechanisms underlying reduction in EDRF/nitric oxide
activity. Circulation. 1992;85:1927-1938.
[Free Full Text]
-
Lynch SM, Morrow JD, Roberts LJ, Frei B.
Formation of non-cyclooxygenase-derived
prostanoids (F2-isoprostanes) in plasma and low density
lipoprotein exposed to oxidative stress in vitro. J
Clin Invest. 1994;93:998-1004.
-
Parthasarathy S, Steinberg D, Witztum JL. The
role of oxidized low-density lipoproteins in the pathogenesis of
atherosclerosis. Annu Rev Med. 1992;43:219-225. [Medline]
[Order article via Infotrieve]
-
Regnström J, Nilsson J, Tornvall P, Landou C,
Hamsten A. Susceptibility to low-density lipoprotein
oxidation and coronary atherosclerosis in
man. Lancet. 1992;339:1183-1186. [Medline]
[Order article via Infotrieve]
-
Maggi E, Chiesa R, Melissano G, Castellano R, Astore D,
Grossi A, Finardi G, Bellomo G. LDL oxidation in patients with
severe carotid atherosclerosis: a study of in vitro and
vivo oxidation markers. Arterioscler
Thromb. 1994;14:1892-1899.
[Abstract/Free Full Text]
This article has been cited by other articles:
 |
|
 |
|
  F. Palm, M. L. Onozato, Z. Luo, and C. S. Wilcox Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3227 - H3245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Yang, C. B. Ambrosone, C.-C. Hong, J. Ahn, C. Rodriguez, M. J. Thun, and E. E. Calle Relationships between polymorphisms in NOS3 and MPO genes, cigarette smoking and risk of post-menopausal breast cancer Carcinogenesis, June 1, 2007; 28(6): 1247 - 1253. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Barac, U. Campia, and J. A. Panza Methods for Evaluating Endothelial Function in Humans Hypertension, April 1, 2007; 49(4): 748 - 760. [Full Text] [PDF]
|
|
|
|
|
|
E. Takimoto and D. A. Kass Role of Oxidative Stress in Cardiac Hypertrophy and Remodeling Hypertension, February 1, 2007; 49(2): 241 - 248. [Full Text] [PDF]
|
|
|
|
 |
|
 A Dagre, J Lekakis, C Mihas, A Protogerou, L Thalassinou, D Tryfonopoulos, G Douridas, C Papamichael, and M Alevizaki Association of dehydroepiandrosterone-sulfate with endothelial function in young women with polycystic ovary syndrome. Eur. J. Endocrinol., June 1, 2006; 154(6): 883 - 890. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Raupach, K. Schafer, S. Konstantinides, and S. Andreas Secondhand smoke as an acute threat for the cardiovascular system: a change in paradigm Eur. Heart J., February 2, 2006; 27(4): 386 - 392. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. S. Perlstein and R. T. Lee Smoking, Metalloproteinases, and Vascular Disease Arterioscler. Thromb. Vasc. Biol., February 1, 2006; 26(2): 250 - 256. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Bendall, N. J. Alp, N. Warrick, S. Cai, D. Adlam, K. Rockett, M. Yokoyama, S. Kawashima, and K. M. Channon Stoichiometric Relationships Between Endothelial Tetrahydrobiopterin, Endothelial NO Synthase (eNOS) Activity, and eNOS Coupling in Vivo: Insights From Transgenic Mice With Endothelial-Targeted GTP Cyclohydrolase 1 and eNOS Overexpression Circ. Res., October 28, 2005; 97(9): 864 - 871. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Bernhard, A. Csordas, B. Henderson, A. Rossmann, M. Kind, and G. Wick Cigarette smoke metal-catalyzed protein oxidation leads to vascular endothelial cell contraction by depolymerization of microtubules FASEB J, July 1, 2005; 19(9): 1096 - 1107. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Shoenfeld, R. Wu, L. D. Dearing, and E. Matsuura Are Anti-Oxidized Low-Density Lipoprotein Antibodies Pathogenic or Protective? Circulation, October 26, 2004; 110(17): 2552 - 2558. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Matsumoto, H. Takashima, N. Ohira, Y. Tarutani, Y. Yasuda, T. Yamane, S. Matsuo, and M. Horie Plasma level of oxidized low-density lipoprotein is an independent determinant of coronary macrovasomotor and microvasomotor responses induced by bradykinin J. Am. Coll. Cardiol., July 21, 2004; 44(2): 451 - 457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Jarvisalo, M. Raitakari, J. O. Toikka, A. Putto-Laurila, R. Rontu, S. Laine, T. Lehtimaki, T. Ronnemaa, J. Viikari, and O. T. Raitakari Endothelial Dysfunction and Increased Arterial Intima-Media Thickness in Children With Type 1 Diabetes Circulation, April 13, 2004; 109(14): 1750 - 1755. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.D. Booth, D.R.W. Jayne, R.K. Kharbanda, C.M. McEniery, I.S. Mackenzie, J. Brown, and I.B. Wilkinson Infliximab Improves Endothelial Dysfunction in Systemic Vasculitis: A Model of Vascular Inflammation Circulation, April 13, 2004; 109(14): 1718 - 1723. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. J. Alp and K. M. Channon Regulation of Endothelial Nitric Oxide Synthase by Tetrahydrobiopterin in Vascular Disease Arterioscler. Thromb. Vasc. Biol., March 1, 2004; 24(3): 413 - 420. [Abstract] [Full Text]
|
|
|
|
 |
|
 F. J. Nieto, D. M. Herrington, S. Redline, E. J. Benjamin, and J. A. Robbins Sleep Apnea and Markers of Vascular Endothelial Function in a Large Community Sample of Older Adults Am. J. Respir. Crit. Care Med., February 1, 2004; 169(3): 354 - 360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. Engler, M. B. Engler, M. J. Malloy, E. Y. Chiu, M. C. Schloetter, S. M. Paul, M. Stuehlinger, K. Y. Lin, J. P. Cooke, J. D. Morrow, et al. Antioxidant Vitamins C and E Improve Endothelial Function in Children With Hyperlipidemia: Endothelial Assessment of Risk from Lipids in Youth (EARLY) Trial Circulation, September 2, 2003; 108(9): 1059 - 1063. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Tsiara, M. Elisaf, and D. P. Mikhailidis Influence of Smoking on Predictors of Vascular Disease Angiology, September 1, 2003; 54(5): 507 - 530. [Abstract] [PDF]
|
|
|
|
|
|
G. Reaven and P. S. Tsao Insulin resistance and compensatory hyperinsulinemia: The key player between cigarette smoking and cardiovascular disease? J. Am. Coll. Cardiol., March 19, 2003; 41(6): 1044 - 1047. [Abstract] [Full Text] [PDF]
|
|
|
|