| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 1995;91:941-947.)
© 1995 American Heart Association, Inc.
Articles |
Tissue Endothelin-1 Immunoreactivity in the Active Coronary Atherosclerotic Plaque
A Clue to the Mechanism of Increased Vasoreactivity of the Culprit Lesion in Unstable Angina
From the Department of Internal Medicine III, Division of Cardiology (A.M.Z., H.G., V.S.), and the Department of Pathology (C.I.), University of Freiburg (Germany).
Correspondence to Andreas M. Zeiher, MD, Department of Internal Medicine III, Division of Cardiology, University of Freiburg, Hugstetterstr 55, D-79106 Freiburg, Germany.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Background The pathomorphological substrate of complicated coronary atherosclerotic lesions underlying unstable angina is characterized by a localized chronic inflammatory process. Functionally, coronary lesions associated with unstable angina demonstrate an enhanced vasoreactivity. Endothelin-1 is a potent vasoconstrictor peptide produced not only by endothelial cells but also by macrophages and polymorphonuclear leukocytes, the cell types characteristic of inflammation.
Methods and Results By use of immunohistochemical
techniques, we examined the presence of endothelin-1 in coronary
atherosclerotic plaque tissue obtained by directional coronary
atherectomy of primary lesions from 50 consecutive patients. The tissue
specimens of 43 of 50 patients (86%) demonstrated endothelin-1–like
immunoreactivity. Endothelin-1–like immunoreactivity preferentially
localized to macrophage-rich areas, to hypercellular regions rich in
microvessels, and to plaque areas with evidence of prior hemorrhage.
Double-immunolabeling revealed that both macrophages (HAM56 positive)
and intimal smooth muscle cells (
-actin positive) demonstrated
cytoplasmic immunostaining for endothelin-1. Semiquantitative
analysis of endothelin-1–like immunostaining revealed
significantly (P<.005) higher staining grades in active
(1.86±0.15, n=40) compared with nonactive lesions
(0.78±0.35, n=10):
endothelin-1 staining grades were significantly (P<.001)
lower in patients with stable angina (0.69±0.19, n=13) than in
patients with crescendo angina (1.82±0.30, n=11), with angina at
rest
(2.08±0.21, n=12), or with angina after myocardial infarction
(2.0±0.26, n=14).
Conclusions Endothelin-1 immunostaining of atherosclerotic tissue localizes predominantly with plaque components indicative of chronic inflammatory processes. The increased tissue endothelin-1–like immunoreactivity in active coronary atherosclerotic lesions may provide a clue to the mechanisms of increased vasoreactivity of the culprit lesion in acute ischemic syndromes, which is the clinical substrate of the active coronary atherosclerotic plaque.
Key Words: atherosclerosis • endothelin • angina • leukocytes • ischemia
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Plaque rupture, hemorrhage, and thrombus formation have been implicated as the mechanisms responsible for the transformation of stable coronary lesions into active lesions,1 2 leading to unstable angina, acute myocardial infarction, and sudden ischemic death. The pathomorphological substrate underlying a complicated lesion appears to be related to plaque composition.1 3 Although plaque morphology is heterogeneous with respect to plaque architecture and cellular composition, the presence of a localized inflammatory process is a characteristic consistently associated with plaque rupture.4 5
The active coronary atherosclerotic lesion is characterized functionally by an abnormal vasoconstriction6 manifested as exaggerated constrictor responses to platelet mediators.7 Importantly, a recent study demonstrated that enhanced coronary vasoreactivity in unstable angina is confined to the culprit lesion,8 suggesting that enhanced vasoreactivity is a local plaque–related phenomenon rather than the consequence of systemically operative neurohumoral factors.
Endothelin-1 is one of a family of peptides that are potent constrictors of vascular smooth muscle.9 10 In addition to being a potent vasoconstrictor itself, endothelin-1 markedly potentiates the constrictor effects of other vasoconstrictor stimuli, such as catecholamines, serotonin, and angiotensin II.11 12 13 Interestingly, endothelin-1 is not only produced by endothelial cells but also by human macrophages14 and polymorphonuclear leukocytes,15 suggesting a role for endothelin-1 in inflammatory processes.
Thus, the present study was designed to examine the presence of endothelin-1 in the active coronary atherosclerotic plaque as a potential clue to the mechanism of increased vasoreactivity of the culprit lesion in unstable angina.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Patients
Atherosclerotic lesions from 50 consecutive patients undergoing percutaneous revascularization for the first time (primary lesions) between August 1992 and May 1994 were analyzed. Atherectomy specimens were retrieved by therapeutic directional coronary atherectomy with the Simpson AtheroCath (DVI) according to previously described techniques.16 Patients with evidence of significant narrowing (>75%) of a major epicardial artery and lesion anatomy suitable for directional atherectomy were included in the study. The mean age of the patients was 57±8 years; 8 were women and 42 were men. Lesions were located in the left anterior descending coronary artery in 40 patients, in the right coronary artery in 7, and in the left circumflex artery in 3. Thirteen patients had stable angina, defined as stable angina pectoris for at least 3 months before percutaneous revascularization; 11 had crescendo angina, defined as accelerated angina pectoris during the past 2 months; 12 had angina at rest, defined as angina pectoris occurring at rest within 5 days before percutaneous revascularization; and 14 had postinfarction angina, defined as angina pectoris within the first 3 weeks after an acute myocardial infarction. In all patients with acute ischemic syndromes, the culprit lesion was treated by directional atherectomy.
Tissue Preparation
All atherectomy specimens retrieved were
fixed in 4% unbuffered
formalin at the time of percutaneous revascularization. Tissue was
dehydrated in graded series of alcohol and embedded in a paraffin
block. Serial sections were stained for hematoxylin and eosin,
elastica–van Gieson's stain, and Perls' iron stain (Prussian
blue
reaction). Serial unstained sections were used for
immunohistochemistry.
Immunohistochemistry
Sections embedded in paraffin were cut
and mounted on slides.
The slides were dried overnight at 60°C, deparaffinized with graded
concentrations of xylene and ethanol, and washed with 0.6%
H2O2 in methanol for 30 minutes at room
temperature to block endogenous peroxidase activity. Tissue was then
incubated with 5% normal bovine serum for 10 minutes at room
temperature to reduce nonspecific background staining and then with a
rabbit polyclonal endothelin-1 antiserum diluted 1:250 (Peninsula) in
humidified chambers for 2 hours at room temperature. The specificity of
this antibody has been extensively validated in previous
studies.17 18 All treated slides were then incubated
with
biotinylated secondary antibody at room temperature followed by
incubation with avidin and biotinylated horseradish peroxidase complex
(ABC method, Vector Labs). Peroxidase activity was visualized by
3-amino-9-ethylcarbazole. The sections were counterstained with
hematoxylin. As a positive control for endothelin-1, human internal
mammary artery sections with preserved endothelial cell layers were
used; these sections gave the expected well-localized pattern within
endothelial cells, with negative staining of subintimal and medial
layers.
Cell types were determined in serial sections with monoclonal
antibodies specific to either smooth muscle -actin (dilution,
1:1000; Sigma Immunochemicals) or macrophages (HAM56; dilution, 1:50;
Enzo Diagnostics Inc).
Double-Label Immunohistochemistry
To identify specific cell
types expressing endothelin-1–like
immunoreactivity, double labeling was performed with endothelin-1
antibody and a cell-specific antibody. Briefly, the single-label
procedure was performed as described above with
3-amino-9-ethylcarbazole to yield a brownish reaction product. In a
second step, either -actin or HAM56 staining was performed with the
alkaline phosphatase and monoclonal antialkaline phosphatase
method.19 Activity of alkaline phosphatase was visualized
with naphthol AS-MX phosphate (Sigma N 4875) and fast blue BB salt
(Sigma F 3378) substrate solution to yield a blue reaction product.
Activity of endogenous alkaline phosphatase was blocked by adding 0.01
mL of 1 mol/L levamisole (Sigma L 9756) to the substrate solution.
Since it has been shown that HAM56 also recognizes endothelial cells,
we used a different antibody specific for macrophages, CD68 (Dako), in
experiments in which microvessels were present in the tissue
specimens. In general, HAM56 and CD68 gave identical results except in
some areas with neovascularization, in which HAM56 occasionally also
stained endothelial cells of the microvessels.
Histochemical and Immunohistochemical Analysis
The specimens
were analyzed by light microscopy for the presence
of thrombus, old hemorrhage (positive Prussian blue reaction),
atheromatous gruel surrounded by macrophages indicative of inflammatory
processes, abundant and disorganized smooth muscle cells in the
presence of loose connective tissue, and neovascularization. A lesion
was classified as active if one or more of the criteria mentioned above
were met. These sections were examined for the presence and
localization of endothelin-1–like immunoreactivity. Comparative
examination of serial sections permitted the assessment of
colocalization of endothelin-1–like immunoreactivity with intimal
smooth muscle cells (-actin positive) and macrophages (HAM56 or CD68
positive). Double labeling was used to confirm the simultaneous
presence of both antigens in the cell cytoplasm, as indicated by a
brownish and blue staining. In addition, endothelin-1 immunostaining
intensity was graded semiquantitatively from 0 to 3: grade 0 indicated
the absence of any staining; grade 1, endothelin-1 positivity
associated with <10% of the cells; grade 2, positivity of 10% to
30% of the cells; and grade 3, positivity of >30% of the cells.
Grading was performed independently by two of the investigators (H.G.,
C.I.) who were without knowledge of the clinical symptoms. The grades
independently assigned by both observers agreed to within one grade;
differences were resolved by joint examination.
Statistical Analysis
All data are reported as mean±SEM
unless stated otherwise.
One-way ANOVA followed by the Student-Newman test was used for
statistical comparison. For dichotomous variables, we used Fisher's
exact or the 
2 test. The exact two-sided
Jonckheere-Terpstra test20 was used to compare the
distribution of different plaque characteristics within different
patient groups. A value of P<.05 was considered
statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Endothelin-1 Labeling
The specimens of 43 of the 50 patients (86%) contained material that was immunostainable for endothelin-1. Endothelin-1–like immunoreactivity was distributed focally, with a preferential localization to three histologically defined components of the plaque: macrophage-rich areas surrounding atheromatous gruel; hypercellular regions rich in microvessels adjacent to areas of macrophage infiltration; and areas with evidence of old hemorrhage, as evidenced by a positive Prussian blue reaction. Fig 1
illustrates
the characteristic distribution of endothelin-1 immunoreactivity in a
tissue specimen exhibiting all the criteria mentioned above.
Endothelin-1 immunostaining appeared in two distinct patterns:
cytoplasmic and diffuse extracellular staining (Fig 1). Diffuse
extracellular staining was frequently observed in necrotic areas,
suggesting that endothelin-1 was derived from previously injured or
dead cells. In contrast, endothelin-1 immunostaining that localized to
macrophages surrounding necrotic areas or to hypercellular areas of
intimal smooth muscle cells was exclusively found in the cytoplasm. Fig
2 illustrates cytoplasmic endothelin-1 immunostaining in
an area of abundant disorganized smooth muscle cells in the presence of
loose connective tissue. Double-labeling confirmed that both
macrophages and intimal smooth muscle cells demonstrated cytoplasmic
immunostaining for endothelin-1 (Fig 3).
|
|
|
In the
vascularized regions, cells that appeared to be endothelial
stained inconsistently for endothelin-1 (Fig 1G
). However,
extensive
endothelin-1 immunostaining was found in hypercellular regions adjacent
to microvessels and preferentially localized to areas of old
hemorrhage, as evidenced by a positive Prussian blue reaction (Fig
4).
|
Endothelin-1 immunostaining was weak in hypocellular fibrotic regions and, whenever present, preferentially localized to scattered macrophages.
In 33 patients, the tissue specimens contained regions of necrotic gruel. Of these, 31 (94%) were also positive for endothelin-1–like immunoreactivity, whereas endothelin-1 immunostaining was observed in only 9 of 17 patients (53%) without necrotic material in their atherectomy specimens (P<.05). All atherectomy specimens with microvessels (those from 23 patients) were also positive for endothelin-1 immunostaining, whereas endothelin-1 staining was found in only 16 of 27 patients (59%) without neovascularization in their excised coronary atherosclerotic tissue (P<.05). Thirty of 35 (86%) patients with evidence of old hemorrhage had material immunostainable for endothelin-1, and in 9 of 15 patients (60%), endothelin-1 immunostaining was observed in the absence of a positive Prussian blue reaction (P=NS). Thrombi were found in the tissue specimens of 28 patients, of whom 23 (82%) were also positive for endothelin-1 staining, whereas 17 of 22 patients (77%) demonstrated endothelin-1 immunostaining without evidence of thrombotic material. The tissue specimens of 11 patients consisted predominantly of hypocellular fibrotic material, whereas 39 patients had either mixed or hypercellular lesions with a predominance of smooth muscle cells. Endothelin-1 immunostaining was detected in only 6 patients (55%) with fibrotic lesions (n=11) but in 37 of 39 patients (95%) with mixed or hypercellular lesions (P<.01).
Semiquantitative Analysis of Endothelin-1 Immunostaining
Fig
5 illustrates the mean endothelin-1 staining
grades with respect to the presence or absence of different
well-defined plaque components. The degree of endothelin-1 staining was
significantly greater in lesions containing necrotic areas and
neovascularization but significantly lower in predominantly
hypocellular fibrotic lesions. On the basis of histological plaque
components, the lesions of 40 patients were classified as active; the
mean endothelin-1 staining grade was significantly (P<.005)
higher in these active lesions (1.86±0.15) compared with a mean
endothelin-1 staining grade of 0.78±0.35 (P<.005) in the
nonactive lesions (n=10).
|
Correlation of Endothelin-1 Staining With Clinical Symptoms
Fig 6 illustrates the endothelin-1 staining grades
for each individual lesion in the four groups of patients with
different anginal symptoms. Endothelin-1 staining grades were
significantly (P<.001) lower in patients with stable angina
(0.69±0.19) compared with patients with crescendo angina
(1.82±0.30),
with angina at rest (2.08±0.21), and with postinfarction angina
(2.0±0.26). At the same time, lesion activity was significantly
(P<.001) higher in the patients with crescendo angina and
acute ischemic syndromes compared with patients with stable angina, as
assessed by the distribution of the histological characteristics
necrosis, thrombus, old hemorrhage, and neovascularization within the
four groups with different anginal syndromes (Fig 7).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
This study was designed to identify and quantify the content of endothelin-1–like immunoreactivity of human coronary atherosclerotic plaque tissue. The results reveal that the active coronary atherosclerotic plaque is characterized by the presence of significant amounts of tissue endothelin-1–like immunoreactivity. Endothelin-1 immunostaining localizes predominantly to areas with extensive macrophage infiltration and to hypercellular regions with evidence for neovascularization in the vicinity of atheromatous gruel. The association of tissue endothelin-1 immunoreactivity with plaque components indicative of chronic inflammatory responses suggests a role for local inflammatory processes in the production of endothelin-1 within atherosclerotic lesions.
A role for endothelin-1 in inflammation has been suggested by experimental findings that demonstrated that endothelin-1 production is induced by lipopolysaccharides in human macrophages14 and that endothelin-1 is synthesized and degraded by polymorphonuclear leukocytes.15 Moreover, increased tissue endothelin-1 levels have been observed in the submucosa of patients with chronic inflammatory bowel disease.21 Atherosclerosis is increasingly thought to be a chronic inflammatory disease22 23 characterized by foci of macrophages and T lymphocytes in the arterial wall, by the proliferation of vascular smooth muscle cells, and by matrix formation and neovascularization.24 Previous studies in humans have shown the presence of endothelin-1–like immunoreactivity in vascular smooth muscle cells of the atherosclerotic aorta17 and an increase in endothelin-1 mRNA in atherosclerotic carotid lesions,25 suggesting an activation of the endothelin-1 gene in atherosclerosis and providing a rational basis for the observation of increased plasma levels of endothelin-1 correlating with the severity of atherosclerosis.17 The present study is the first to assess endothelin-1–like immunoreactivity and its localization to specific cell types within the atherosclerotic plaque. Endothelin-1 immunostaining was most prominent in areas with evidence of macrophage infiltration. Macrophages are the principal inflammatory cells in atherosclerotic plaques, and their role as key mediators involved in the transition of stable atherosclerotic lesions into active lesions is well established.4 5 The results of the present study, demonstrating an association of endothelin-1 immunostaining with macrophage-rich plaque areas indicative of active inflammatory responses, provide compelling new evidence in support of the view that endothelin-1 not only is generally involved in inflammatory processes in vivo but also is particularly involved in active coronary atherosclerotic lesions.
A role for inflammatory processes in the expression of tissue endothelin-1 in atherosclerotic plaque is also supported by our findings that, in the vicinity of atheromatous gruel, increased tissue endothelin-1 immunoreactivity was observed in hypercellular regions with evidence for neovascularization, which are also characteristic histological features of a chronic inflammatory response. Macrophages not only contribute to the disruption of the atherosclerotic plaque but also secrete mitogenic factors leading to the proliferation of smooth muscle cells and stimulation of plaque neovascularization.1 26 27 The finding of an association of increased tissue endothelin-1 immunoreactivity with hypercellular areas rich in microvessels is intriguing. Previous studies implicated that microvessels may contribute to plaque evolution or complication by means of intraplaque hemorrhages.28 29 Dividing cells exhibiting positive staining for proliferating cell nuclear antigen as an indicator of ongoing growth factor activity localize preferentially in areas of microvascularization.30 Hemosiderin deposits located near intimal microvessels, as demonstrated in the present study and as reported by others,29 suggest the occurrence of prior hemorrhage. The newly formed vascular channels may themselves be prone to rupture or cause intraplaque hemorrhage after plaque fracture with subsequent in situ thrombosis, activating thrombin-mediated events. Thrombin and an as yet unidentified platelet-derived regulatory factor have been shown to be potent inducers of endothelin production.31 32 Endothelin-1 is a potent mitogen for vascular smooth muscle cells in vitro33 34 and induces the expression and release of several proto-oncogenes and growth factors, the latter of which may be synergistic.35 36 37 Indeed, endothelin-1 has recently been shown to promote neointimal formation in a rat model of balloon angioplasty.38 The finding that tissue endothelin-1 immunoreactivity colocalizing with intimal smooth muscle cells was most abundant in hypercellular regions rich in microvessels suggests that the localization of endothelin-1 in the atherosclerotic plaque may reflect the site of atheroma progression of primary atherosclerotic lesions. In addition, plaque microvessels also provide a large surface area, which can promote further recruitment of mononuclear cells and thus contribute to the evolution of the atherosclerotic plaque by magnifying inflammatory responses.
The presence of endothelin-1–like immunoreactivity in the atherosclerotic plaque could reflect an internalization of endothelin-1 produced by endothelial cells39 or the active production of endothelin-1 by intimal smooth muscle cells or macrophages.14 40 Previous experimental studies have demonstrated that oxidatively modified low-density lipoproteins activate human monocyte–derived macrophages to secrete immunoreactive endothelin-1 by activation of protein kinase C.14 41 Since oxidized low-density lipoproteins accumulate within the vessel wall, especially in areas of atheromatous gruel,42 the preferential colocalization of endothelin-1 immunoreactivity with macrophages surrounding atheromatous gruel supports the view of an increased de novo production of endothelin-1 within the atherosclerotic plaque rather than internalization of endothelin-1 produced by endothelial cells. Importantly, blood-derived monocytes did not stain for endothelin-1–like immunoreactivity (data not shown), indicating functional differences compared with macrophages residing in plaque.
Clinical Implications
The active coronary lesion is the
pathological substrate of the
clinical syndrome of unstable angina.1 The culprit lesion
in unstable angina exhibits a greater vasoconstrictor potential
compared with a stable coronary artery lesion.8 43
Previous studies aimed at elucidating the pathophysiology underlying
exaggerated vasoconstriction in unstable angina have focused mainly on
impaired vasodilation due to endothelial dysfunction with loss or
impaired diffusion of endothelium-derived relaxing
factors through the altered vascular wall.44 Endothelial
injury has been shown to promote platelet-dependent vasoconstriction
mediated by serotonin and thromboxane A2 and
thrombin-dependent vasoconstriction.44 However,
endothelial vasodilator dysfunction, manifested as paradoxical
constriction to endothelium-dependent vasodilator
agonists such as acetylcholine or serotonin, is present already in
very early stages of
atherosclerosis.45 46 47 Thus, although
impaired endothelial vasodilator function undoubtedly predisposes for
platelet- and thrombin-dependent vasoconstriction at the site of plaque
disruption and thrombosis, these abnormalities of coronary vasomotor
response, related simply to the presence of atherosclerotic plaques,
are by themselves likely to play only a modulating rather than a major
role in impairing coronary blood flow in unstable
angina.48 Indeed, we have previously shown that
intracoronary thrombus formation is associated with only moderate
degrees of vasoconstriction of human atherosclerotic coronary arteries
in vivo and never caused occlusive spasm.49 Similarly,
ergometrine induced occlusive spasm at the site of preexisting stenoses
in only 4% of patients with stable angina but in as many as 36% of
patients with angina at rest.43 These findings suggest
that the coincidental presence of a local coronary artery
hyperreactivity may be a crucial factor for the exaggerated constrictor
responses observed in unstable angina. Importantly, previous studies
have demonstrated that threshold concentrations of endothelin-1
sensitize the vasculature to a variety of vasoconstrictor stimuli, such
as serotonin, norepinephrine, and angiotensin
II.11 12 13 In
addition, Lerman et al18 recently reported a close
correlation between the degree of acetylcholine-induced coronary
vasoconstriction and elevated plasma endothelin concentrations in
parallel with enhanced endothelin immunoreactivity in the coronary
vascular wall of hypercholesterolemic pigs. On the basis of these
results, increases in local tissue concentrations of endothelin-1 could
very likely be responsible for the segmental coronary hyperreactivity
observed in unstable angina. Thus, endothelin-1 could not only enhance
vascular tone by itself but also could amplify the contractions induced
by other vasoconstrictors leading to arterial spasm upon
stimulation.
Most importantly, the advent of endothelin receptor antagonists, which are currently in phase 1 clinical evaluation, offers a direct, novel therapeutic strategy and ultimately will define the precise role of this peptide in pathophysiological consequences of unstable angina.
In summary, the results of the present study demonstrate that the active coronary atherosclerotic lesion is characterized by an increase in tissue endothelin-1–like immunoreactivity. Endothelin-1 immunostaining localizes predominantly with plaque components indicative of chronic inflammatory processes. Despite potential sampling limitations,50 the increased tissue endothelin-1 content may provide a clue to the mechanism of increased vasoreactivity of the culprit lesion in unstable angina, which is the clinical substrate of the active coronary atherosclerotic plaque.
Received November 8, 1994; accepted November 25, 1994.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Fuster V, Badimon L, Badimon JJ, Chesebro JH. Mechanisms of disease: the pathogenesis of coronary artery disease and the acute coronary syndromes (part one). N Engl J Med. 1992;326:242-250. [Medline] [Order article via Infotrieve]
2.
Falk E. Unstable angina with fatal outcome: dynamic coronary
thrombosis leading to infarction and/or sudden death.
Circulation. 1985;71:699-708.
3. Richardson PD, Davies MJ, Born GV. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaque. Lancet. 1989;2:941-944. [Medline] [Order article via Infotrieve]
4.
van der Wal AC, Becker AE, van der Loos CM, Das PK. Site of
intimal rupture or erosion of thrombosed coronary atherosclerotic
plaques is characterized by an inflammatory process irrespective of the
dominant plaque morphology. Circulation. 1994;89:36-44.
5.
Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon
JT. Macrophage infiltration in acute coronary syndromes: implications
for plaque rupture. Circulation. 1994;90:775-778.
6. Fuster V, Badimon L, Badimon JJ, Chesebro JH. Mechanisms of disease: the pathogenesis of coronary artery disease and the acute coronary syndromes (part two). N Engl J Med. 1992;326:310-318. [Medline] [Order article via Infotrieve]
7.
Willerson JT, Golino P, Eidt J, Campbell WB, Buja LM.
Specific platelet mediators and unstable coronary artery lesions:
experimental evidence and potential clinical implications.
Circulation. 1989;80:198-205.
8.
Bogarty P, Hackett D, Davies G, Maseri A. Vasoreactivity of
the culprit lesion in unstable angina.
Circulation. 1994;90:5-11.
9. Yangiasawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411-415. [Medline] [Order article via Infotrieve]
10. Inoue A, Yangiasawa M, Kimura S, Kasuya Y, Niyauchi T, Goto K, Masaki T. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci U S A. 1989; 86:2863-2867.
11.
Yang Z, Richard D, Von Segesser L, Bauer E, Stulz P, Turina M,
Lüscher TF. Threshold concentrations of endothelin-1 potentiate
contractions to norepinephrine and serotonin in human arteries: a new
mechanism of vasospasm? Circulation. 1990;82:188-195.
12. Tabuchi Y, Nakamura M, Rakugi H, Nagano M, Ogihara T. Endothelin enhances adrenergic vasoconstriction in perfused rat mesenteric arteries. Biochem Biophys Res Commun. 1989; 159:1304-1308.
13.
Dohi Y, Hahn AWA, Boulanger CM, Bühler FR, Lüscher
TF. Endothelin stimulated by angiotensin II augments contractility of
spontaneously hypertensive rat resistance arteries.
Hypertension. 1992;19:131-137.
14.
Ehrenreich H, Andreson RW, Fox CH, Rieckmann P, Hoffman GS,
Travis WD, Coligan JE, Kehrl JH, Fauci AS. Endothelins, peptides with
potent vasoactive properties, are produced by human macrophages.
J Exp Med. 1990;172:1741-1748.
15. Sessa WC, Kaw S, Hecker M, Vane JR. The biosynthesis of endothelin-1 by human polymorphonuclear leukocytes. Biochem Biophys Res Commun. 1991;174:613-615. [Medline] [Order article via Infotrieve]
16. Hinohara T, Selmon MR, Robertson GC, Braden L, Simpson JB. Directional atherectomy: new approaches for treatment of obstructive coronary and peripheral vascular disease. Circulation. 1990;81(suppl IV):IV-79-IV-91.
17. Lerman A, Edwards BS, Hallett JW, Heublein DM, Sandberg SM, Burnett JC Jr. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med. 1991;325:997-1001. [Abstract]
18.
Lerman A, Webster MWI, Chesebro JH, Edwards WD, Wei C-M,
Fuster V, Burnett JC. Circulating and tissue endothelin
immunoreactivity in hypercholesterolemic pigs.
Circulation. 1993;88:2923-2928.
19. Cordell JL, Falini B, Erber WN, Ghosh AK, Abdulaziz Z, MacDonald S, Pulford KA, Stein H, Mason DY. Immunoenzymatic labelling of monoclonal antibodies using immune complexes of alkaline phosphatase and monoclonal anti-alkaline phosphatase (APAAP complexes). J Histochem Cytochem. 1984;32:219-229. [Abstract]
20. Hollander M, Wolfe DA. Nonparametric Statistical Methods. New York, NY: John Wiley; 1973:198.
21. Murch SH, Braegger CP, Sessa WC, MacDonald TT. High endothelin-1 immunoreactivity in Crohn's disease and ulcerative colitis. Lancet. 1992;339:381-385. [Medline] [Order article via Infotrieve]
22. Munro JM, Cotran RS. The pathogenesis of atherosclerosis: atherogenesis and inflammation. Lab Invest. 1988;58:249-261. [Medline] [Order article via Infotrieve]
23.
Alexander RW. Inflammation and coronary artery disease.
N Engl J Med. 1994;331:468-469. Editorial.
24. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801-809. [Medline] [Order article via Infotrieve]
25. Winkles JA, Alberts GF, Brogi E, Libby P. Endothelin-1 and endothelin receptor mRNA expression in normal and atherosclerotic human arteries. Biochem Biophys Res Commun. 1993;191: 1081-1088.
26. Mitchinson MJ, Ball RY. Macrophages and atherogenesis. Lancet. 1987;2:146-148. [Medline] [Order article via Infotrieve]
27.
Steinberg D. Antioxidants and atherosclerosis.
Circulation. 1991;84:1420-1425.
28. Barger AC, Beeuwwkes R, Lainey LL, Siverman KJ. Hypothesis: vasa vasorum and neovascularization of human coronary arteries. N Engl J Med. 1984;310:175-177. [Medline] [Order article via Infotrieve]
29. Imparato AM, Riles TS, Mintzer R, Baumann FG. The importance of hemorrhage in the relationship between gross morphologic characteristics and cerebral symptoms in 376 carotid artery plaques. Ann Surg. 1982;197:195-203.
30. Brogi E, Winkles JA, Underwood R, Clinton SK, Alberts GF, Libby P. Distinct patterns of expression of fibroblast growth factors and their receptors in human atheroma and nonatherosclerotic arteries. Association of acidic FGF with plaque microvessels and macrophages. J Clin Invest. 1993;92:2408-2418.
31.
Boulanger CM, Tanner FC, Bea ML, Hahn AWA, Werner A,
Lüscher T. Oxidized low density lipoproteins induce mRNA
expression and release of endothelin from human and porcine
endothelium. Circ Res. 1992;70:1191-1197.
32.
Ohlstein EH, Storer JA, Debouck C, Feuerstein G. Platelets
stimulate expression of endothelin mRNA and endothelin biosynthesis in
cultured endothelial cells. Circ Res. 1991;69:832-841.
33. Miller WL, Redfield MM, Burnett JC Jr. Integrated cardiac, renal, and endocrine actions of endothelin. J Clin Invest. 1989;83:317-320.
34. Dubin D, Pratt RE, Cooke JP, Dzau VJ. Endothelin, a potent vasoconstrictor, is a vascular smooth muscle mitogen. J Vasc Med Biol. 1989;1:150-154.
35. Komura I, Kurihara H, Sugiyama T, Takafu F, Yazaki Y. Endothelin stimulates c-fos and c-myc expression and proliferation of vascular smooth muscle cells. FEBS Lett. 1988;238:249-252. [Medline] [Order article via Infotrieve]
36.
Bobik A, Grooms A, Millar JA, Mitchell A, Grinpukel S. Growth
factor activity of endothelin on vascular smooth muscle. Am J
Physiol. 1990;258:C408-C415.
37. Scott-Burden T, Resink TJ, Hahn AWA, Vanhoutte PM. Induction of endothelin secretion by angiotensin II: effects on growth and synthetic activity of vascular smooth muscle cells. J Cardiovasc Pharmacol. 1991;17(suppl 7):S96-S100.
38.
Douglas SA, Louden C, Vickery-Clark LM, Storer BL, Hart T,
Feuerstein GZ, Elliott JD, Ohlstein EH. A role for endogenous
endothelin-1 in neointimal formation after rat carotid
artery balloon angioplasty. Circ Res. 1994;75:190-197.
39. Resink TJ, Scott-Burden T, Boulanger C, Weber E, Bühler FR. Internalization of endothelin by cultured human vascular smooth muscle cells: characterization and physiological significance. Mol Pharmacol. 1990;38:244-252. [Abstract]
40. Resink TJ, Hahn AWA, Scott-Burden T, Powell J, Weber E, Bühler FR. Inducible endothelin mRNA expression and peptide secretion in cultured human vascular smooth muscle cells. Biochem Biophys Res Commun. 1990;168:1303-1310. [Medline] [Order article via Infotrieve]
41. Martin-Nizard F, Houssaini HS, Lestavel-Delattre S, Duriez P, Fruchart J-C. Modified low density lipoproteins activate human macrophages to secrete immunoreactive endothelin. FEBS Lett. 1991;293:127-130. [Medline] [Order article via Infotrieve]
42. Ylä-Herttuala S, Palinski W, Rosenfeld ME, Parthasarathy C, Carew TE, Butler S, Witzum JL, Steinberg D. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest. 1989;84:1086-1095.
43.
Bertrand ME, La Blanche JM, Tilmant PY, Thieuleux FA, Delfarge
MR, Carre G, Asseman P, Berzin B, Libersa C, Laurent JM. Frequency of
provoked coronary arterial spasm in 1089 consecutive patients
undergoing coronary arteriography. Circulation. 1982;65:1299-1306.
44.
Vanhoutte PM, Shimokawa H. Endothelium-derived relaxing factor
and coronary vasospasm. Circulation. 1989;80:1-9.
45.
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.
46.
Zeiher AM, Drexler H, Wollschläger H, Just H. Modulation
of coronary vasomotor tone: progressive endothelial dysfunction with
different early stages of coronary atherosclerosis.
Circulation. 1991;83:391-401.
47. McFadden EP, Clarke JG, Davies GJ, Kaski JC, Haider AW, Maseri A. Effect of intracoronary serotonin on coronary vessels in patients with stable angina and patients with variant angina. N Engl J Med. 1991;324:648-654. [Abstract]
48.
Maseri A, Davies G, Hackett D, Kaski JC. Coronary artery spasm
and vasoconstriction: the case for a distinction.
Circulation. 1990;81:1983-1991.
49.
Zeiher AM, Schächinger V, Weitzel SH, Wollschläger
H, Just H. Intracoronary thrombus formation causes focal
vasoconstriction of epicardial arteries in patients with coronary
artery disease. Circulation. 1991;83:1519-1525.
50. Waller BF, Pinkerton CA. `Cutters, scoopers, hovers and scrappers': the importance of atherectomy devices and clinical relevance of tissue removed. J Am Coll Cardiol. 1990;15:426-428.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  D. W. Anggrahini, N. Emoto, K. Nakayama, B. Widyantoro, S. Adiarto, N. Iwasa, H. Nonaka, Y. Rikitake, Y. Y. Kisanuki, M. Yanagisawa, et al. Vascular endothelial cell-derived endothelin-1 mediates vascular inflammation and neointima formation following blood flow cessation Cardiovasc Res, April 1, 2009; 82(1): 143 - 151. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. M. Loke, J. M Hodgson, J. M Proudfoot, A. J McKinley, I. B Puddey, and K. D Croft Pure dietary flavonoids quercetin and (-)-epicatechin augment nitric oxide products and reduce endothelin-1 acutely in healthy men Am. J. Clinical Nutrition, October 1, 2008; 88(4): 1018 - 1025. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Ahlborg, A. Shemyakin, F. Bohm, A. Gonon, and J. Pernow Dual Endothelin Receptor Blockade Acutely Improves Insulin Sensitivity in Obese Patients With Insulin Resistance and Coronary Artery Disease Diabetes Care, March 1, 2007; 30(3): 591 - 596. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Niccoli, G. A. Lanza, S. Shaw, E. Romagnoli, D. Gioia, F. Burzotta, C. Trani, M. A. Mazzari, R. Mongiardo, M. De Vita, et al. Endothelin-1 and acute myocardial infarction: a no-reflow mediator after successful percutaneous myocardial revascularization Eur. Heart J., August 1, 2006; 27(15): 1793 - 1798. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Ramzy, V. Rao, L. C. Tumiati, N. Xu, R. Sheshgiri, S. Miriuka, D. H. Delgado, and H. J. Ross Elevated Endothelin-1 Levels Impair Nitric Oxide Homeostasis Through a PKC-Dependent Pathway Circulation, July 4, 2006; 114(1_suppl): I-319 - I-326. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhou, S. Mitra, S. Varadharaj, N. Parinandi, J. L. Zweier, and N. A. Flavahan Increased Expression of Cyclooxygenase-2 Mediates Enhanced Contraction to Endothelin ETA Receptor Stimulation in Endothelial Nitric Oxide Synthase Knockout Mice Circ. Res., June 9, 2006; 98(11): 1439 - 1445. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Jackson, K. Barnes, S. Homer-Vanniasinkam, and A. J. Turner Expression and localization of human endothelin-converting enzyme-1 isoforms in symptomatic atherosclerotic disease and saphenous vein. Experimental Biology and Medicine, June 1, 2006; 231(6): 794 - 801. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Gossl and A. Lerman Endothelin: Beyond a Vasoconstrictor Circulation, March 7, 2006; 113(9): 1156 - 1158. [Full Text] [PDF]
|
|
|
|
|
|
A. J. Sutherland, M. I. Nataatmadja, P. J. Walker, L. Cuttle, R. B. Garlick, and M. J. West Vascular Remodeling in the Internal Mammary Artery Graft and Association With In Situ Endothelin-1 and Receptor Expression Circulation, March 7, 2006; 113(9): 1180 - 1188. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Tomai, F. Ribichini, A. S. Ghini, V. Ferrero, G. Ando, C. Vassanelli, F. Romeo, F. Crea, and L. Chiariello Elevated C-reactive protein levels and coronary microvascular dysfunction in patients with coronary artery disease Eur. Heart J., October 2, 2005; 26(20): 2099 - 2105. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Lerman and A. M. Zeiher Endothelial Function: Cardiac Events Circulation, January 25, 2005; 111(3): 363 - 368. [Full Text] [PDF]
|
|
|
|
 |
|
 F Tomai C reactive protein and microvascular function Heart, July 1, 2004; 90(7): 727 - 728. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Rich and V. V. McLaughlin Endothelin Receptor Blockers in Cardiovascular Disease Circulation, November 4, 2003; 108(18): 2184 - 2190. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Maeda, T. Tanabe, T. Miyauchi, T. Otsuki, J. Sugawara, M. Iemitsu, S. Kuno, R. Ajisaka, I. Yamaguchi, and M. Matsuda Aerobic exercise training reduces plasma endothelin-1 concentration in older women J Appl Physiol, July 1, 2003; 95(1): 336 - 341. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Nohria, L. Garrett, W. Johnson, S. Kinlay, P. Ganz, and M. A. Creager Endothelin-1 and Vascular Tone in Subjects With Atherogenic Risk Factors Hypertension, July 1, 2003; 42(1): 43 - 48. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Wolfrum, K. S. Jensen, and J. K. Liao Endothelium-Dependent Effects of Statins Arterioscler Thromb Vasc Biol, May 1, 2003; 23(5): 729 - 736. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Kudaiberdieva, B. Timuralp, N. Ata, A. Unalir, B. Gorenek, Y. Cavusoglu, O. Goktekin, and A. Birdane Cold Exposure and Left Ventricular Diastolic Performance In Coronary Artery Disease Angiology, March 1, 2003; 54(2): 187 - 193. [Abstract] [PDF]
|
|
|
|
|
|
P.O Bonetti, L.O Lerman, C Napoli, and A Lerman Statin effects beyond lipid lowering--are they clinically relevant? Eur. Heart J., February 1, 2003; 24(3): 225 - 248. [Full Text] [PDF]
|
|
|
|
|
|
P. O. Bonetti, L. O. Lerman, and A. Lerman Endothelial Dysfunction: A Marker of Atherosclerotic Risk Arterioscler Thromb Vasc Biol, February 1, 2003; 23(2): 168 - 175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Ahlborg and J. Lindstrom Insulin sensitivity and big ET-1 conversion to ET-1 after ETA- or ETB-receptor blockade in humans J Appl Physiol, December 1, 2002; 93(6): 2112 - 2121. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Mangiafico, L. S. Malatino, T. Attina, R. Messina, and C. E. Fiore Exaggerated Endothelin Release in Response to Acute Mental Stress in Patients with Intermittent Claudication Angiology, July 1, 2002; 53(4): 383 - 390. [Abstract] [PDF]
|
|
|
|
|
|
U. Kelkenberg, A. H. Wagner, J. Sarhaddar, M. Hecker, and H. E. von der Leyen CCAAT/Enhancer-Binding Protein Decoy Oligodeoxynucleotide Inhibition of Macrophage-Rich Vascular Lesion Formation in Hypercholesterolemic Rabbits Arterioscler Thromb Vasc Biol, June 1, 2002; 22(6): 949 - 954. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Bohm, G. Ahlborg, B.-L. Johansson, L.-O. Hansson, and J. Pernow Combined Endothelin Receptor Blockade Evokes Enhanced Vasodilatation in Patients With Atherosclerosis Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 674 - 679. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Lockowandt, S. Bjessmo, T. Ivert, and A. Franco-Cereceda Plasma levels and vascular effects of endothelin and big endothelin in patients with stable and unstable angina pectoris undergoing coronary bypass grafting Eur. J. Cardiothorac. Surg., February 1, 2002; 21(2): 218 - 223. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. P. Metsarinne, P. Vehmaan-Kreula, P. T. Kovanen, O. Saijonmaa, M. Baumann, Y. Wang, T. Nyman, F. Y. Fyhrquist, and K. K. Eklund Activated Mast Cells Increase the Level of Endothelin-1 mRNA in Cocultured Endothelial Cells and Degrade the Secreted Peptide Arterioscler Thromb Vasc Biol, February 1, 2002; 22(2): 268 - 273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Taylor, A. Bobik, M. C. Berndt, D. Ramsay, and G. Jennings Experimental Rupture of Atherosclerotic Lesions Increases Distal Vascular Resistance: A Limiting Factor to the Success of Infarct Angioplasty Arterioscler Thromb Vasc Biol, January 1, 2002; 22(1): 153 - 160. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Tomai, F. Crea, A. Gaspardone, F. Versaci, A. S. Ghini, L. Chiariello, and P. A. Gioffre Unstable Angina and Elevated C-Reactive Protein Levels Predict Enhanced Vasoreactivity of the Culprit Lesion Circulation, September 25, 2001; 104(13): 1471 - 1476. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kinlay, D. Behrendt, M. Wainstein, J. Beltrame, J. C. Fang, M. A. Creager, A. P. Selwyn, and P. Ganz Role of Endothelin-1 in the Active Constriction of Human Atherosclerotic Coronary Arteries Circulation, September 4, 2001; 104(10): 1114 - 1118. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Gaspardone Endothelin: a new marker of risk of rapid coronary stenosis progression in patients with stable angina? Eur. Heart J., September 1, 2001; 22(17): 1519 - 1520. [PDF]
|
|
|
|
|
|
E.G. Zouridakis, R. Schwartzman, X. Garcia-Moll, I.D. Cox, S. Fredericks, D.W. Holt, and J.C. Kaski Increased plasma endothelin levels in angina patients with rapid coronary artery disease progression Eur. Heart J., September 1, 2001; 22(17): 1578 - 1584. [Abstract] [PDF]
|
|
|
|
|
|
C. Ihling, T. Szombathy, B. Bohrmann, M. Brockhaus, H. E. Schaefer, and B. M. Loeffler Coexpression of Endothelin-Converting Enzyme-1 and Endothelin-1 in Different Stages of Human Atherosclerosis Circulation, August 21, 2001; 104(8): 864 - 869. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. E. Spieker, G. Noll, F. T. Ruschitzka, and T. F. Luscher Endothelin receptor antagonists in congestive heart failure: a new therapeutic principle for the future? J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1493 - 1505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Haug, A. Schmid-Kotsas, U. Zorn, M. G. Bachem, S. Schuett, A. Gruenert, and E. Rozdzinski Hepatocyte growth factor is upregulated by low-density lipoproteins and inhibits endothelin-1 release Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H2865 - H2871. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. F. Luscher and M. Barton Endothelins and Endothelin Receptor Antagonists : Therapeutic Considerations for a Novel Class of Cardiovascular Drugs Circulation, November 7, 2000; 102(19): 2434 - 2440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Babaei, P. Picard, A. Ravandi, J. C. Monge, T. C. Lee, P. Cernacek, and D. J. Stewart Blockade of endothelin receptors markedly reduces atherosclerosis in LDL receptor deficient mice: role of endothelin in macrophage foam cell formation Cardiovasc Res, October 1, 2000; 48(1): 158 - 167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Ruschitzka, U. Moehrlen, T. Quaschning, M. Lachat, G. Noll, S. Shaw, Z. Yang, D. Teupser, T. Subkowski, M. I. Turina, et al. Tissue Endothelin-Converting Enzyme Activity Correlates With Cardiovascular Risk Factors in Coronary Artery Disease Circulation, September 5, 2000; 102(10): 1086 - 1092. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Marzilli, G. Sambuceti, S. Fedele, and A. L'Abbate Coronary microcirculatory vasoconstriction during ischemia in patients with unstable angina J. Am. Coll. Cardiol., February 1, 2000; 35(2): 327 - 334. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. M. Best, L. O. Lerman, J. C. Romero, D. Richardson, D. R. Holmes Jr, and A. Lerman Coronary Endothelial Function Is Preserved With Chronic Endothelin Receptor Antagonism in Experimental Hypercholesterolemia In Vitro Arterioscler Thromb Vasc Biol, November 1, 1999; 19(11): 2769 - 2775. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Gobel, C. Ihling, J. Dentz, H. E. Schaefer, A. M. Zeiher, and G. Fraedrich Increased tissue endothelin-1-like immunoreactivity in the internal mammary artery of patients with diabetes or hypercholesterolemia modulates the graft flow in the peri-operative period Eur. J. Cardiothorac. Surg., October 1, 1999; 14(4): 367 - 372. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Iwasaki, S. Eguchi, H. Ueno, F. Marumo, and Y. Hirata Endothelin-Mediated Vascular Growth Requires p42/p44 Mitogen-Activated Protein Kinase and p70 S6 Kinase Cascades via Transactivation of Epidermal Growth Factor Receptor Endocrinology, October 1, 1999; 140(10): 4659 - 4668. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. C. Doherty and M. A. McMillen Vulnerable Plaque Ann Intern Med, September 7, 1999; 131(5): 393 - 393. [Full Text] [PDF]
|
|
|
|
|
|
I. J. Kullo, W. D. Edwards, and R. S. Schwartz Vulnerable Plaque Ann Intern Med, September 7, 1999; 131(5): 393 - 394. [Full Text] [PDF]
|
|
|
|
|
|
M. Borries, M. Heins, Y. Fischer, H. Stiegler, A. Peters, H. Reinauer, F. C. Schoebel, B. E. Strauer, and M. Leschke Changes of hemostasis, endogenous fibrinolysis, platelet activation and endothelins after percutaneous transluminal coronary angioplasty in patients with stable angina J. Am. Coll. Cardiol., August 1, 1999; 34(2): 486 - 493. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Caligiuri, B. Levy, J. Pernow, P. Thoren, and G. K. Hansson Myocardial infarction mediated by endothelin receptor signaling in hypercholesterolemic mice PNAS, June 8, 1999; 96(12): 6920 - 6924. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Tiret, O. Poirier, V. Hallet, T. A. McDonagh, C. Morrison, J. J. V. McMurray, H. J. Dargie, D. Arveiler, J.-B. Ruidavets, G. Luc, et al. The Lys198Asn Polymorphism in the Endothelin-1 Gene Is Associated With Blood Pressure in Overweight People Hypertension, May 1, 1999; 33(5): 1169 - 1174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.-L. Tharaux, C. Chatziantoniou, D. Casellas, L. Fouassier, R. Ardaillou, and J.-C. Dussaule Vascular Endothelin-1 Gene Expression and Synthesis and Effect on Renal Type I Collagen Synthesis and Nephroangiosclerosis During Nitric Oxide Synthase Inhibition in Rats Circulation, April 27, 1999; 99(16): 2185 - 2191. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. M. Best, C. J. McKenna, D. Hasdai, D. R. Holmes Jr, and A. Lerman Chronic Endothelin Receptor Antagonism Preserves Coronary Endothelial Function in Experimental Hypercholesterolemia Circulation, April 6, 1999; 99(13): 1747 - 1752. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. P. Rossi, S. Colonna, E. Pavan, G. Albertin, F. Della Rocca, G. Gerosa, D. Casarotto, S. Sartore, P. Pauletto, and A. C. Pessina Endothelin-1 and Its mRNA in the Wall Layers of Human Arteries Ex Vivo Circulation, March 9, 1999; 99(9): 1147 - 1155. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. C. van der Wal and A. E. Becker Atherosclerotic plaque rupture - pathologic basis of plaque stability and instability Cardiovasc Res, February 1, 1999; 41(2): 334 - 344. [Full Text] [PDF]
|
|
|
|
|
|
M. Barton, C. C. Haudenschild, L. V. d'Uscio, S. Shaw, K. Munter, and T. F. Luscher Endothelin ETA receptor blockade restores NO-mediated endothelial function and inhibits atherosclerosis in apolipoprotein E-deficient mice PNAS, November 24, 1998; 95(24): 14367 - 14372. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Kirchengast and K. Munter Endothelin and restenosis Cardiovasc Res, September 1, 1998; 39(3): 550 - 555. [Full Text] [PDF]
|
|
|
|
|
|
B. Geny, F. Piquard, J. Lonsdorfer, and P. Haberey Endothelin and heart transplantation Cardiovasc Res, September 1, 1998; 39(3): 556 - 562. [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Liao Endothelium and acute coronary syndromes Clin. Chem., August 1, 1998; 44(8): 1799 - 1808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Matsuura, W. Yamochi, K.-i. Hirata, S. Kawashima, and M. Yokoyama Stimulatory Interaction Between Vascular Endothelial Growth Factor and Endothelin-1 on Each Gene Expression Hypertension, July 1, 1998; 32(1): 89 - 95. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Allen, M. Dashwood, K. Morrison, and M. Yacoub Differential Leukotriene Constrictor Responses in Human Atherosclerotic Coronary Arteries Circulation, June 23, 1998; 97(24): 2406 - 2413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ziegler, K. Bouzourene, V. J. Harrison, H. R. Brunner, and D. Hayoz Influence of Oscillatory and Unidirectional Flow Environments on the Expression of Endothelin and Nitric Oxide Synthase in Cultured Endothelial Cells Arterioscler Thromb Vasc Biol, May 1, 1998; 18(5): 686 - 692. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-J. Hwang, C. M. Ballantyne, A. R. Sharrett, L. C. Smith, C. E. Davis, A. M. Gotto Jr, and E. Boerwinkle Circulating Adhesion Molecules VCAM-1, ICAM-1, and E-selectin in Carotid Atherosclerosis and Incident Coronary Heart Disease Cases : The Atherosclerosis Risk In Communities (ARIC) Study Circulation, December 16, 1997; 96(12): 4219 - 4225. [Abstract] [Full Text]
|
|
|
|
|
|
K. Sudhir, E. Ko, C. Zellner, H. E. Wong, S. J. Hutchison, T. M. Chou, and K. Chatterjee Physiological Concentrations of Estradiol Attenuate Endothelin 1–Induced Coronary Vasoconstriction In Vivo Circulation, November 18, 1997; 96(10): 3626 - 3632. [Abstract] [Full Text]
|
|
|
|
|
|
S. Kapiotis, B. Jilma, T. Szalay, E. Dirnberger, O. Wagner, H.-G. Eichler, and W. Speiser Evidence Against an Effect of Endothelin-1 on Blood Coagulation, Fibrinolysis, and Endothelial Cell Integrity in Healthy Men Arterioscler Thromb Vasc Biol, November 1, 1997; 17(11): 2861 - 2867. [Abstract] [Full Text]
|
|
|
|
|
|
M. D. Guazzi, M. Bussotti, L. Grancini, N. De Cesare, M. Guazzi, I. L. Pera, and A. Loaldi Evidence of Multifocal Activity of Coronary Disease in Patients With Acute Myocardial Infarction Circulation, August 19, 1997; 96(4): 1145 - 1151. [Abstract] [Full Text]
|
|
|
|
|
|
D. Hasdai, D. R. Holmes, K. N. Garratt, W. D. Edwards, and A. Lerman Mechanical Pressure and Stretch Release Endothelin-1 From Human Atherosclerotic Coronary Arteries In Vivo Circulation, January 21, 1997; 95(2): 357 - 362. [Abstract] [Full Text]
|
|
|
|
|
|
T. Minamino, H. Kurihara, M. Takahashi, K. Shimada, K. Maemura, H. Oda, T. Ishikawa, T. Uchiyama, K. Tanzawa, and Y. Yazaki Endothelin-Converting Enzyme Expression in the Rat Vascular Injury Model and Human Coronary Atherosclerosis Circulation, January 7, 1997; 95(1): 221 - 230. [Abstract] [Full Text]
|
|
|
|
|
|
U. Ikeda, K. Yamamoto, Y. Maeda, M. Shimpo, T. Kanbe, and K. Shimada Endothelin-1 Inhibits Nitric Oxide Synthesis in Vascular Smooth Muscle Cells Hypertension, January 1, 1997; 29(1): 65 - 69. [Abstract] [Full Text]
|
|
|
|
|
|
X. Wang, C. Louden, E. H. Ohlstein, J. M. Stadel, J.-L. Gu, and T.-L. Yue Osteopontin Expression in Platelet-Derived Growth Factor–Stimulated Vascular Smooth Muscle Cells and Carotid Artery After Balloon Angioplasty Arterioscler Thromb Vasc Biol, November 1, 1996; 16(11): 1365 - 1372. [Abstract] [Full Text]
|
|
|
|
|
|
S. Ravalli, M. Szabolcs, A. Albala, R. E. Michler, and P. J. Cannon Increased Immunoreactive Endothelin-1 in Human Transplant Coronary Artery Disease Circulation, November 1, 1996; 94(9): 2096 - 2102. [Abstract] [Full Text]
|
|
|
|
|
|
C. R. Bacon, N. R.B. Cary, and A. P. Davenport Endothelin Peptide and Receptors in Human Atherosclerotic Coronary Artery and Aorta Circ. Res., October 1, 1996; 79(4): 794 - 801. [Abstract] [Full Text]
|
|
|
|
|
|
R. R. Wenzel, N. Duthiers, G. Noll, J. Bucher, U. Kaufmann, and T. F. Luscher Endothelin and Calcium Antagonists in the Skin Microcirculation of Patients With Coronary Artery Disease Circulation, August 1, 1996; 94(3): 316 - 322. [Abstract] [Full Text]
|
|
|
|
|
|
S. Kaddoura, J. D. Firth, K. R. Boheler, P. H. Sugden, and P. A. Poole-Wilson Endothelin-1 Is Involved in Norepinephrine-Induced Ventricular Hypertrophy In Vivo : Acute Effects of Bosentan, an Orally Active, Mixed Endothelin ETA and ETB Receptor Antagonist Circulation, June 1, 1996; 93(11): 2068 - 2079. [Abstract] [Full Text]
|
|
|
|
|
|
X. Wang, S. A. Douglas, C. Louden, L. M. Vickery-Clark, G. Z. Feuerstein, and E. H. Ohlstein Expression of Endothelin-1, Endothelin-3, Endothelin-Converting Enzyme-1, and Endothelin-A and Endothelin-B Receptor mRNA After Angioplasty-Induced Neointimal Formation in the Rat Circ. Res., February 1, 1996; 78(2): 322 - 328. [Abstract] [Full Text]
|
|
|
|
|
|
F. Bohm, G. Ahlborg, B.-L. Johansson, L.-O. Hansson, and J. Pernow Combined Endothelin Receptor Blockade Evokes Enhanced Vasodilatation in Patients With Atherosclerosis Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 674 - 679. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Ferri, G. Properzi, G. Tomassoni, A. Santucci, G. Desideri, A. E. Giuliani, R. C. Starling, N. B. Ratliff, D. J. Cook, P. McCarthy, et al. Patterns of Myocardial Endothelin-1 Expression and Outcome After Cardiac Transplantation Circulation, April 16, 2002; 105(15): 1768 - 1771. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||