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Current Vascular Pharmacology
ISSN: 1570-1611
Current Vascular Pharmacology
Volume 3, Number 4, October 2005
Contents
Editorial Pp.305
Endothelin-1 and Angiogenesis in Cancer Pp.309
Jonathan Knowles, Marilena Loizidou and Irving Taylor
[Abstract]
The Pathobiology of Endothelin-1 in Vein Graft
Disease: Are ETA Receptor Antagonists the Solution to Prevent
Vein Graft Failure? Pp.315
Jamie Y. Jeremy, Nilima Shukla, Song Wan, Gavin Murphy,
Gianni D. Angelini, Anthony Yim and Michael R. Dashwood
[Abstract]
A Role for Endothelin-1 in Peripheral Vascular Disease Pp.325
Janice C.S. Tsui and Michael R. Dashwood
[Abstract]
Endothelin and the Ischaemic Heart Pp.333
Cherry L. Wainwright, Christopher McCabe and Kathleen
A. Kane
[Abstract]
Endothelin Signalling in the Cardiac Myocyte and its
Pathophysiological Relevance Pp.343
Peter H. Sugden and Angela Clerk
[Abstract]
Endothelin-1 and the Aortic Valve Pp.353
Adrian H. Chester
[Abstract]
Insulin Resistance, Obesity and the Metabolic Syndrome.
Is There a Therapeutic Role for Endothelin-1 Antagonists?
Pp.359
Sidney G. Shaw and P. Jane Boden
[Abstract]
Endothelin and Oxidative Stress in the Vascular System
Pp.365
David M. Pollock and Jennifer S. Pollock
[Abstract]
Connective Tissue Remodelling: Cross-talk between
Endothelins and the MMPs and TIMPs Pp.369
David Abraham, Markella Ponticos and Hideaki Nagase
[Abstract]
Localisation of Endothelin-1 and its Receptors in
Vascular Tissue as Seen at the Electron Microscopic Level
Pp.381
Andrzej Loesch
[Abstract]
Endothelin-1 and Human Platelets Pp.393
I. Anita Jagroop, Stella S. Daskalopoulou and Dimitri
P. Mikhailidis
[Abstract]
Abstracts
[Back to top]
Editorial
This supplement of Current Vascular Pharmacology, “The
endothelin system: vascular targets for therapy in disease”,
is a special issue that coincides with the Ninth International
Conference on Endothelin to be held in Park City, Utah, USA
from September 11 – 14, 2005 (http://www.med.utah.edu/et9/).
Over the past 17 years, research into many aspects of the
endothelins (ETs) has generated considerable interest since
the classical paper of Yanagisawa et al. was published
in Nature [1].
Eight biannual International Conferences on the ETs have
been held with the venues being shared by three continents.
The first Endothelin 1 (ET-1), was hosted in 1989 by the late
Sir John Vane at the William Harvey Institute in London. Subsequent
meetings have been held in Tsukuba, Japan (ET-2 in 1991);
Houston, USA (ET-3 in 1993); London, UK (ET-4 in 1995); Kyoto,
Japan (ET-5 in 1997); Montreal, Canada (ET-6 in 1999); Edinburgh,
UK (ET-7 in 2001) and Tsukuba, Japan (ET-8 in 2003). Short
papers of proceedings from these meetings have been published
as supplements of the Journal of Cardiovascular Pharmacology
and Clinical Science.
Today, the field of ET research continues to attract the
interest of both basic and clinical scientists with the number
of ET-related publications approaching 18,000, including approximately
850 reviews. The announcement by Dr Martine Clozel, at the
Edinburgh Conference in 2001, that Actelion had been granted
FDA approval for bosentan (a ‘dual’ ET receptor
antagonist) to undergo clinical trial for pulmonary hypertension
caused great excitement and added impetus into studying the
therapeutic potential of other compounds interfering with
the pathophysiological effects of the ETs. Apart from pulmonary
hypertension [2], other conditions being targeted include
prostate cancer [3], melanoma [4] and digital ulceration [5].
While many of the scientists involved in the early years
of ET research have moved towards other areas, this issue
of Current Vascular Pharmacology contains peer-reviewed articles
written by internationally recognised scientists whose contributions
address important topics relevant to the journal, including
the role of ET in various aspects of heart and vascular disease,
diabetes, tissue fibrosis and cancer.
In many instances, there are similarities in the mechanisms
underlying these conditions. For example, the role of ET in
cancer angiogenesis described in the article by Knowles
et al. (1) suggests that ET-1 has a pathophysiological
role in ‘feeding’ tumours, whereas the articles
by Jeremy and colleagues (2) and Tsui and Dashwood (3) discuss
the potential benefits of ET-1-induced microvascular growth
in preserving vein graft patency and restoring blood flow
to skeletal muscle in patients with peripheral vascular disease.
Initially, ET-1 was described as the most potent vasoconstrictor
known via its action on vascular smooth muscle cells [1].
The potential role of ET-1-mediated constriction in various
pathological conditions is discussed in this supplement. In
the review by Wainwright et al. (4), the role of
ET-1 in myocardial ischaemia and reperfusion in various experimental
animal models is described, whereas Tsui and Dashwood (3)
present evidence that ET-1 is involved in lower limb ischaemia
and peripheral vascular disease, a condition that in severe
cases requires leg amputation. Apart from the effect of ET-1
on coronary vessels, Wainwright et al. (4) discuss
its arrhythmogenic action on cardiac cells, whereas Sugden
and Clerk (5) provide an overview of ET’s effects on
cardiac myocytes at the gene transcription level. The contribution
by Chester (6) presents some novel findings on the effect
of ET on the structure and function of the aortic valve and
the potential of endothelial cell-derived ET-1 to stimulate
the contractile responses of heart valve cusps.
Various aspects of vascular disease are covered in this supplement.
Shaw and Boden (7) describe raised ET-1 levels associated
with the development of insulin resistance, obesity and the
metabolic syndrome, with consequent effects on vasoreactivity
and endothelial cell dysfunction suggesting that ET antagonists
may have therapeutic potential in such conditions. Additional
actions of ET-1 on the vascular system may be mediated via
reactive oxygen species, and the potential contribution of
ET-1-induced superoxide production is discussed in the review
by David and Jennifer Pollock (8).
All the ET-1-induced effects described above are mediated
via ETA or ETB receptors, or both. The effects of either selective
or dual receptor antagonists are discussed by most contributors
to this supplement. For example, Wainwright et al.
(4) refer to studies showing that ETA-selective and dual receptor
antagonists reduce infarct size in animal models of heart
ischaemia and reperfusion injury and that ET-1-induced arrhythmias
are blocked by ETA-selective antagonists. Sugden and Clerk
(5) provide additional evidence that ETA receptors are involved
in the regulation of c-Jun expression and phosphorylation
in rat cardiac myocytes, where ET-1 plays an important role
in the regulation of gene transcription. In addition, Wainwright
and colleagues (4) and Tsui and Dashwood (3) discuss the beneficial
action of ET receptor antagonists in ischaemic conditions,
with evidence suggesting that targeting the ETA receptor would
be desirable.
A part from the ETA receptor playing a predominant role in
ET-1-induced vasoconstriction, this receptor also plays an
important role in ET-1-induced cell proliferation. For example,
Jeremy et al. (2) show that ETA receptor blockade
is effective at reducing graft failure in a porcine saphenous
vein into carotid artery interposition graft model. This effect
is mainly due to the inhibition of vascular smooth muscle
cell proliferation that leads to neointimal formation, reduced
lumen size and eventual graft occlusion. Similar beneficial
effects have been described previously where selective ETA
antagonist treatment reduces neointimal formation and restenosis
following balloon angioplasty in porcine coronary arteries
[6].
The effect of ET-1 on extracellular matrix formation and
vessel remodelling in vein graft failure is also discussed
in the review by Jeremy et al. (2), in particular
the role of this peptide in activating the matrix metalloproteinases
(MMPs). A more detailed account of the role of both MMPs and
their ‘natural’ inhibitors, the tissue inhibitors
of metalloproteinases (TIMPs) is provided by Abraham et
al. (9). In their contribution, these authors review
various studies into the effect of ET-1 on remodelling of
connective tissue via its action on MMPs and TIMPs. Of the
three ET isoforms (ET-1, ET-2 and ET-3), ET-1 has the most
potent effect on these compounds with most evidence indicating
that these effects are mediated via the ETA receptor subtype.
Apart from the interaction between ET-1, MMPs and TIMPs in
the cardiovascular system, an association with both extracellular
matrix formation and tumour biology is also covered in this
section.
Many early publications suggest that ET-1 is a ‘pathophysiological’
peptide, and this was supported by evidence from Martine Clozel’s
group who, in their Nature paper [7], refer to the use of
the first orally active ET receptor antagonist (bosentan)
to reveal the pathophysiological role of endogenously-released
ET-1 in various animal models. Subsequently, many studies
have been performed and many publications have discussed the
therapeutic potential of ET receptor antagonists (both selective
and dual). However, there is compelling evidence that, via
its ‘physiological’ effects, ET-1 may also be
a ‘good guy’ [8] (see also Wainwright et al
4). For example, ET-1 has been shown to be involved in the
local maintenance of vascular tone [9], endothelium-dependent
release of nitric oxide [10], and neovascularisation [8,11],
and it has been suggested that endogenous ET-1 contributes
to plaque stabilisation in atherosclerosis [8]. In addition,
studies using ET-1 knockout mice showed craniofacial abnormalities
at birth [12], suggesting that ET-1 plays an important role
in foetal development. This has also been supported by studies
using ET receptor knock out mice. Mice lacking the ETA receptor
exhibit both cranial and neural crest defects [13], whereas
ETB receptors are implicated in intestinal aganglionosis in
a rat model of Hirschsprung disease [14]. Clearly, interference
with endogenous ET-1 may be detrimental in certain cases where
antagonist administration would produce undesirable effects.
Future attempts to overcome such problems may require more
refined techniques such as gene targeting or the use of local
delivery using drug-eluting stents.
In an attempt to identify sites where ET-1 acts, various
techniques have been used to study the localisation and distribution
of ET-1 and its receptors in both normal and diseased tissue.
The review by Tsui and Dashwood (3) identifies ET-1 and ETA/ETB
receptors in skeletal muscle microvessels in patients with
peripheral vascular disease, where ETA receptors predominate
on the vascular smooth muscle, the site of ET-1-induced vasoconstriction.
ETB receptors, however, are associated with endothelial cells,
where ET-1 may cause vasodilatation via endothelium-derived
nitric oxide release, or angiogenesis. While these observations
are made at the light microscopic level, elegant studies in
the review by Loesch (10) extend such findings to the ultrastructural
level using electron microscopy. Here, examples of ET-1-positive
immunostaining are shown in human cerebral artery, rat coronary
artery and rat liver carcinoma. An important finding in these
studies is the identification of ET-1-containing vesicles
in perivascular nerves, potential non-endothelial sources
of the peptide.
Additional novel data are in the contribution by Jagroop
et al. (11) who have shown that ET-1 is a potent
activator of platelets. As an important constituent of circulating
blood, platelets not only play a role in the clotting process
and thrombus formation, but are also the source of a variety
of factors affecting vascular tone, cell adhesion and vascular
smooth muscle cell proliferation. There is conflicting published
data in this area, and future studies are clearly needed to
establish the therapeutic potential of ET receptor antagonists
in the management of vascular disorders involving platelet
activation.
CONCLUDING COMMENTS
Since the original identification of the ETs and their receptors,
much has been reported regarding the potential role of this
peptide family in a wide variety of both vascular and non-vascular
disorders. However, in his summing up of the London meeting
in 1995, Dr Paul Vanhoutte expressed his disappointment that,
although much work had been performed using the many selective
and non-selective receptor antagonists available at that time,
there was no evidence that any of these compounds possessed
promising therapeutic potential. More recently, a number of
ET receptor antagonists are undergoing clinical trial or are
being prescribed for conditions ranging from pulmonary hypertension
[2] to prostate cancer [3], melanoma [4] and systemic sclerosis
[5].
It will be intriguing to see what new data is presented at
ET-9 in Utah and whether the meeting Chairman, Dr Donald Kohan,
in his closing remarks at this conference will be more optimistic
than Dr Vanhoutte was a decade ago.
ACKNOWLEDGEMENT
Our sincere thanks and appreciation to the editorial team
at Bentham Press, in particular Ms Sadaf Bano, for their help
in producing this special endothelin supplement of Current
Vascular Pharmacology. Also, we are grateful to our colleagues
who have contributed to this issue and to the external international
reviewers for their time and comments that have helped to
produce this issue, which we hope will provide a future source
of reference for various aspects of endothelin research.
REFERENCES
[1] Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi
M, Mitsui Y et al. A novel potent vasoconstrictor
peptide produced by vascular endothelial cells. Nature 1988;332:411-5.
[2] Rubin LH, Badesch DB, Barst RJ, Galie N, Black CM, Keogh
A et al. Bosentan therapy for pulmonary arterial hypertension.
N Engl J Med 2002;346:896-903.
[3] Nelson JB, Hedican SP, George DJ, Reddi AH, Piandosi S,
Eisenberger MA, Simons JW. Identification of endothelin-1
in the pathophysiology of metastatic adenocarcinoma of the
prostate. Nature Med 1995;1:944-9.
[4] Lahav R, Heffner G, Patterson PH. An endothelin B receptor
antagonist inhibits growth and induces cell death in human
melanoma cells in vitro and in vivo. Proc Natl Acad Sci USA
1999;96:11496-11500.
[5] Korn JH, Mayes M, Matucci CM, Rainisio M, Pope J, Hachulla
E et al. Digital ulcers in systemic sclerosis: prevention
by treatment with bosentam an oral endothelin receptor antagonist.
Arthritis Rheum 2004;50:3985-93.
[6] Kirchengast M, Munter K. Endothelin and restenosis. Cardiovasc
Res 1998;39:550-5.
[7] Clozel M, Breu V, Burri K, Cassal JM, Gray G, Hirth G
et al. Pathophysiological role of endothelin revealed
by the first orally active endothelin receptor antagonist.
Nature 1993;365:759-61.
[8] Dashwood MR, Tsui JCS. Endothelin-1 and atherosclerosis:
potential complications associated with endothelin-receptor
blockade. Atherosclerosis 2002;160:297-304.
[9] Webb DJ and Haynes WG. Endothelin as a regulator of cardiovascular
function in health and disease. J Hypertens 1998;16:1081-98.
[10] Rubanyi GM, Polokoff MA. Endothelins: molecular biology,
biochemistry, pharmacology, physiology and pathophysiology.
Pharmacol Rev 1994;46:325-415.
[11] Dashwood MR, Mehta D, Izzat MB, Timm M, Bryan AJ, Angelini
GD, Jeremy JY. Distribution of endothelin-1 (ET-1) receptors
ET(A) and ET(B) and immunoreactive ET-1 in porcine saphenous
vein-carotid artery interposition grafts. Atherosclerosis
1998;137:237-42.
[12] Kurihara Y, Kurihara H, Suzuki H, Kodama T, Maemura K,
Nagai R, Oda H, et al. Elevated blood pressure and
craniofacial abnormalities in mice deficient in endothelin-1.
Nature 1994;368:703-10.
[13] Clouthier DE, Hosoda K, Richardson JA, Williams SC, Yanagisawa
H, Kuwaki T et al. Cranial and cardiac neural crest
defects in endothelin-A receptor-deficient mice. Development
1998;125:813-24.
[14] Gariepy CE, Williams SC, Richardson JA, Emoto N, Williams
SC, Takeda S et al. Transgenic expression of the
endothelin-B receptor prevents congenital intestinal aganglionosis
in a rat model of Hirschprung disease. J Clin Invest 2000;105:1373-82.
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Endothelin-1 and Angiogenesis in Cancer
Jonathan Knowles, Marilena Loizidou and Irving Taylor
Tumours require oxygenation, nutrition and a route for dissemination.
This necessitates the development of new vessels or angiogenesis.
High levels of new vessel development are indicators of poor
prognosis in cancer; they also provide new avenues of anti-tumour
therapy. Angiogenesis in cancer produces structurally different
vessels from angiogenesis in wound healing and inflammation.
This article reviews the differences between vessels in tumour
angiogenesis and ‘normal angiogenesis. The main focus
of the article is the role of the vasoactive peptide endothelin-1
(ET-1) in tumour angiogenesis. The role of ET-1 in tumour
development is reviewed, before the direct and indirect effects
of ET-1 in angiogenesis are examined. ET-1 has a direct angiogenic
effect on endothelial and peri-vascular cells. It also has
an indirect action through the increased release of the potent
pro-angiogenic substance vascular endothelial growth factor
(VEGF), via hypoxia inducible factor-1. ET-1 also indirectly
stimulates angiogenesis by stimulating fibroblasts and cancer
cells to produce pro-angiogenic proteases. ET-1 is a novel
stimulator of tumour angiogenesis and warrants further examination
as an anti-angiogenic treatment target.
[Back to top]
The Pathobiology of Endothelin-1 in Vein Graft Disease:
Are ETA Receptor Antagonists the Solution to Prevent Vein
Graft Failure?
Jamie Y. Jeremy, Nilima Shukla, Song Wan, Gavin Murphy,
Gianni D. Angelini, Anthony Yim and Michael R. Dashwood
Despite the exploration of a large number of disparate drugs
in animal models and clinical trials, no pharma-cological
intervention, with the exception of aggressive lipid lowering
therapy has reduced late vein graft failure in man. The importance
of devising more effective strategies is exemplified by the
considerable economic consequences of vein graft failure.
Worldwide, there are currently more than 1,000,000 coronary
artery bypass graft surgery (CABG) operations a year, the
same number of patients undergoing infrainguinal bypass (IIBS)
for vascular diseases of the lower limb. The pathophysiology
of vein graft failure is complex, involving disparate factors
that include adhesion of platelets and leuko-cytes, rheological
forces, metalloproteinase expression, proliferation and migration
of vascular smooth muscle cells, neointima formation, oxidative
stress, hypoxia and neural re-organisation. Although this
diverse aetiology may seem to preclude any single drug type
as being effective in preventing vein graft failure, one factor
that is involved in every facet of vein graft pathobiology
is endothelin-1 (ET-1). Thus, in this review, we will consider
the diverse aetiology of vein graft disease in relation to
ET-1 and will then present an argument (with evidence) that
ET-1A (ETA) receptor antagonists con-stitute a potentially
effective means of preventing vein graft failure.
[Back to top]
A Role for Endothelin-1 in Peripheral Vascular Disease
Janice C.S. Tsui and Michael R. Dashwood
Peripheral vascular disease can compromise the blood supply
to the lower limb with amputation being neces-sary in severe
cases. Reduced blood flow may be due to arterial occlusive
disease or constriction of skeletal microvessels with the
resultant ischaemia causing pain, tissue damage, ulceration
and gangrene. These events are associated with endo-thelial
damage or dysfunction: endothelin-1 is implicated as a mediator
via its constrictor, proinflammatory and prolifera-tive actions.
Raised plasma and tissue levels of this peptide have been
described in various ischaemic conditions, includ-ing peripheral
vascular disease.
Here, the possible role of endothelin-1 in peripheral vascular
disease is discussed and potential therapeutic tools are con-sidered.
[Back to top]
Endothelin and the Ischaemic Heart
Cherry L. Wainwright, Christopher McCabe and Kathleen
A. Kane
Soon after its identification as a powerful vasoconstrictor
peptide, endothelin (ET-1) was implicated as a detri-mental
agent involved in determining the outcome of myocardial ischaemia
and reperfusion. Early experimental studies demonstrated that
ETA selective and mixed ETA/ETB
receptor antagonists can reduce infarct size and prevent ischaemia-induced
ventricular arrhythmias in models of ischaemia/reperfusion,
implying that ET-1 acts through the ETA receptor
to contribute to injury and arrhythmogenesis. However, as
our understanding of the physiology of ET-1 has expanded,
the role of ET-1 in the ischaemic heart appears ever more
complex. Recent evidence suggests that ET-1 exerts actions
on the heart that are not only detrimental (vasoconstriction,
inhibition of NO production, activation of inflammatory cells),
but which may also contribute to tissue repair, such as inhibition
of cardiomyocyte apoptosis. In addition, ET-1-induced mast
cell degranulation has been linked to a homeostatic mechanism
that controls endogenous ET-1 levels, which may have important
implications for the ischaemic heart. Furthermore the mechanism
by which ET-1 promotes arrhythmogenesis remains controversial.
Some studies imply a direct electrophysiological effect of
ET-1, via ETA receptors, to increase mo-nophasic
action potential duration (MAPD) and induce early after-depolarisations
(EADs), while other studies support the view that coronary
constriction resulting in ischaemia is the basis for the generation
of arrhythmias. Moreover, ET-1 can induce cardioprotection
(precondition) against infarct size and ventricular arrhythmias,
through as yet incompletely un-derstood mechanisms. To enable
us to identify the most appropriate means of targeting this
system in a therapeutically meaningful way we need to continue
to explore the physiology of ET-1, both in the normal and
the ischaemic heart.
[Back to top]
Endothelin Signalling in the Cardiac Myocyte and its
Pathophysiological Relevance
Peter H. Sugden and Angela Clerk
Endothelin A (ETA) transmembrane receptors predominate
in rat cardiac myocytes. These are G protein-coupled receptors
whose actions are mediated by the Gq heterotrimeric
G proteins. Through these, ET-1 binding to ETA-receptors
stimulates the hydrolysis of membrane phosphatidylinositol
4,5-bisphosphate to diacylglycerol and inositol 1,4,5-trisphosphate.
Diacylglycerol remains in the membrane whereas inositol 1,4,5-trisphosphate
is soluble (though its importance in the cardiac myocyte is
still debated). Isoforms of the phospholipid-dependent protein
kinase, protein kinase C (PKC), are intracellular receptors
for diacylglycerol. Cytoplasmic nPKCδ
and nPKCε
detect increases in membrane diacylglycerols and translocate
to the membrane. This brings about PKC activation, though
modifications additional to binding to phospholipids and diacylglycerol
are involved. The next event (probably associated with PKC
activation) is the activation of the membrane-bound small
G protein Ras by exchange of GTP for GDP. Ras.GTP loading
translocates Raf family mitogen-activated protein kinase (MAPK)
kinase kinases to the membrane, initiates the activation of
Raf, and thus activates the extracellular signal-regulated
kinase 1/2 (ERK1/2) cascade. Over longer times, two analogous
protein kinase cascades, the c-Jun N-terminal kinase and p38-mitogen-activated
protein kinase cascades, become activated. As the sig-nals
originating from the ETA receptor are transmitted
through these protein kinase pathways, other signalling molecules
become phosphorylated, thus changing their biological activities.
For example, ET-1 increases the expression of the c-jun
transcription factor gene, and increases abundance and phosphorylation
of c-Jun protein. These changes in c-Jun expression and phosphorylation
are likely to be important in the regulation of gene transcription.
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Endothelin-1 and the Aortic Valve
Adrian H. Chester
The aortic valve is a complex structure, the function of
which is fundamental to sustain life. Previously believed
to be an inert structure that merely opens in response to
the forward flow of blood out of the left ventricle, it is
now established that it is a sophisticated structure with
specific biological properties. However, little is known about
the mechanisms that regulate its function. In this respect,
endothelin is of particular interest due to its range of biological
actions within the cardiovascular system that suggest it may
be capable of stimulating the cells that reside in valve cusps.
Endothelin can be detected in the endothelial cells that cover
valve cusps and it has been demonstrated that it is has the
ability to stimulate contractile responses of cusp tissue
in vitro. These contractions vary with different
regions of the aortic valve cusp and occur preferentially
in the circumferential direction. In addition, evidence exists
that suggests endothelin may also have a role in the morphogenesis
of the aortic valve. Further studies are required to determine
the significance of the effects mediated by endothelin on
cusp tissue to the function of the aortic valve in health
and disease.
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Insulin Resistance, Obesity and the Metabolic Syndrome.
Is there a Thera-peutic Role for Endothelin-1 Antagonists?
Sidney G. Shaw and P. Jane Boden
There is increasing evidence to suggest that chronic activation
of the endothelin-1 system can lead to heterologous desensitization
of the glucose-regulatory and mitogenic actions of insulin
with subsequent development of glucose intolerance, hyperinsulinemia,
impaired endothelial function and exacerbation of cardiovascular
disease. Effects are mediated through a variety of mechanisms
that include attenuation of key insulin signalling pathways
and decreased tyrosine phosphorylation of insulin receptor
substrates IRS-1, SHC and G alpha q/11. Other actions involve
hemodynamic changes leading to reduced delivery of insulin
and glucose to peripheral tissues as well as enhanced hepatic
glycogenolysis, decreased glucose-transporter translocation
and modulation of various adipokines that regulate insulin
action. Overall the data suggest that ET-1 antagonists may
provide an effective means of improving cardiac dysfunction
and favourably influencing glucose tolerance in obese humans
and patients with early insulin sensitivity where there is
clear evidence for activation of the ET-1 system. Although
most effects of ET-1 that modulate mechanisms leading to glucose
intolerance appear to involve the ETA receptor subtype recent
data indicates that combined ETA/ETB receptor antagonists
may function as effectively as selective ETA blockers. Prospective
trials are needed to assess whether ET-1 antagonists, either
alone or in combination, are superior to other more conventional
therapies such as insulin sensitizers and to evaluate effects
of combined treatments on the development of insulin resistance
and the progression of diabetes. Early screening of patients
at risk for evidence of ET-1 activation would help to identify
subjects who may benefit most from such treatment
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Endothelin and Oxidative Stress in the Vascular System
David M. Pollock and Jennifer S. Pollock
Both endothelin(ET)-1 and oxidative stress have been the
subjects of intense investigation within the cardiovascular
field over the past decade and a half, yet little is known
about the precise relationship between these important modulators
of vascular function. There is a firm evidence that ET-1 can
stimulate the production of superoxide via NADPH
oxidase activation, and at the same time, reactive oxygen
species appear to stimulate ET-1 production. What is less
clear is how these changes participate in the pathogenesis
of vascular dysfunction. There is mixed evidence on whether
oxidative stress plays a role in ET-dependent hypertension,
however, a specific influence of ET-induced oxidative stress
to reduce vascular reactivity is more convincing. The current
review summarizes recent investigations into the relationship
between ET-1 and oxidative stress and highlights several areas
that require further investigation.
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Connective Tissue Remodeling: Cross-Talk between Endothelins
and Matrix Metalloproteinases
David Abraham, Markella Ponticos and Hideaki Nagase
Connective tissue remodeling is achieved by a complex process
involving several cell types, a plethora of growth factors,
cytokines, chemokines and turnover of extracellular matrix
(ECM). The main enzymes that degrade ECM molecules are matrix
metalloproteinases (MMPs) and their activities are regulated
by endogenous inhibitors, the tissue inhibitors of metalloproteinases
(TIMPs). Recent studies have indicated that endothelins and
their receptor expression affects tissue remodeling and repair.
Endothelins are rapidly produced by endothelial cells in response
to tissue injury and they have potent vasoconstrictive properties.
They also promote tissue remodeling through activation of
resident connective tissue cells and controlling the production
of MMPs and TIMPs by the activated cells. In this review we
present the cross-talk between the endothelins and the MMP-TIMP
system and their implications in controlling the normal and
abnormal tissue remodeling.
[Back to top]
Localisation of Endothelin-1 and its Receptors in
Vascular Tissue as Seen at the Electron Microscopic Level
Andrzej Loesch
Since the discovery of endothelin in vascular endothelial
cells and its pivotal role in vascular physiology (Yanagisawa
and colleagues [1]), a number of studies have focused on the
localisation of this vasoconstrictor peptide in human and
animal vascular tissue, largely in endothelial cells. Various
vascular beds have been the subject of research in normal
and pathophysiological conditions, for example in neonates,
during ageing, pregnancy, hypertension, diabetes, heart failure,
experimental metastases and neurological disorders. These
studies have revealed the presence of endothelin in the blood
vessel wall, suggesting the involvement of this peptide in
vascular physiology in health and disease. This chapter reviews
studies on the distribution of endothelin-1 (ET-1) and its
receptors (ETA and ETB) in vascular tissue with emphasis on
their ultrastructural localisation.
[Back to top]
Endothelin-1 and Human Platelets
I. Anita Jagroop, Stella S. Daskalopoulou and Dimitri
P. Mikhailidis
There is conflicting evidence regarding the effect of endothelin-1
(ET-1) on platelets. Some studies show that ET-1 activates
platelets, others show platelet inhibition with ET-1 and some
studies did not detect an effect of ET-1. These conflicting
results may be due to complex interactions between platelet
ETA and ETB receptors.
ET-1 antagonism may emerge as an important therapeutic strategy
in the management of several vascular disorders. However,
to date the only prescribed ET-1 antagonist is bosentan for
pulmonary arterial hypertension. Bosentan is a 'dual' ET-1
antagonist (i.e. it acts on both ETA and ETB
receptors). Whether this action involves an effect on platelets
remains to be established.
In this review some of the studies describing the effect
of ET-1 on human platelets are discussed. Vascular diseases
where ET-1 is implicated are also considered.
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