Involvement
of Endothelin-1 in the Pathophysiology of Normal-Tension Glaucoma
Tetsuya Sugiyama
Tetsuya Sugiyama,
Nakano Eye Clinic
of Kyoto Medical Co-operative, 2, Jurakumawari-Higashimachi, Nakagyo-ku, Kyoto
604-8404, Japan
Correspondence to:
Tetsuya Sugiyama, MD, PhD, Nakano Eye Clinic of Kyoto Medical Co-operative, 2,
Jurakumawari-Higashimachi, Nakagyo-ku, Kyoto 604-8404, Japan.
Email:
tsugiyama@kyo-con.or.jp
Telephone: +81-75-801-4151
Fax: +81-75-822-7423
Received: May 21, 2015
Revised: June 27, 2015
Accepted: June 29, 2015
Published online: September 6, 2015
ABSTRACT
In this review, the involvement of endothelin (ET)-1 in
the pathophysiology of normal-tension glaucoma (NTG) is summarized. Several ETs
were first isolated in Japan in 1988, and were identified as some of the most
potent vasoconstrictors. The roles of ETs in the eyes and ocular diseases have
been investigated worldwide. ET-1 is a potential participant in the local
regulation of several fundamental processes, including intraocular pressure
(IOP), ocular blood flow, axonal transport, and neural degeneration. Of these,
the effects on IOP are not addressed in this review, and we instead focus on
the pathophysiology of NTG. Several studies have reported abnormal plasma ET-1
levels or their response to postural changes in NTG. As a chronic ischemic
optic nerve head model induced by ET-1 injections produces retinal ganglion
cell-specific cell death and many cellular changes similar to glaucoma, many
studies have been conducted on neuroprotection for glaucomatous optic
neuropathy using this animal model. Genetic studies on ET receptors have
provided evidence that polymorphisms of ETA and ETB
receptors may be associated with increased NTG risk. In vitro studies have
suggested that ET-1 may cause the death of retinal neurons through glutamate
and nitric oxide synthase. ET-1 further affects the functions of glial and
lamina cribrosa (LC) cells, and may contribute to remodeling of the
extracellular matrix at the LC level in glaucoma. Although few studies have yet
obtained promising results showing that ET receptor antagonists can be
clinically useful for NTG, blockade of ET receptors is a potentially attractive
target for treating this critical ocular disease.
© 2015 ACT. All rights reserved.
Key words: Endothelin-1;
Normal-tension glaucoma; Optic nerve head; Ocular blood flow; Glutamate; Nitric
oxide synthase; Extracellular matrix collagen; Glial cells
Sugiyama T. Involvement of Endothelin-1 in
the Pathophysiology of Normal-Tension Glaucoma. International
Journal of Ophthalmic Research 2015; 1(2): 36-40 Available from: URL:
http://www.ghrnet.org/index.php/ijor/article/view/1221
INTRODUCTION
Endothelins (ETs) were first isolated and identified as potent
vasoconstrictors by a Japanese research group in 1988[1]. The ET
family comprises three isoforms: ET-1, ET-2, and ET-3. ET-1 appears to be the
most biologically potent and predominant member of the ET family, and is
produced by endothelin-converting enzyme (ECE) from a precursor of ET-1, Big
ET-1, in vascular endothelial cells. The production of ET-1 is stimulated by
several factors, including tumor necrosis factor-α, thrombin, and transforming growth
factor-β1. There are at least 4 known ET receptors: ETA, ETB1,
ETB2, and ETC. ETA is a subtype for
vasoconstriction that is found in the smooth muscle tissues of blood vessels.
ETB1 is located in vascular endothelial cells and mediates
vasodilation through the release of other bioactive substances such as nitric
oxide. ETB2 mediates vasoconstriction[2]. The function of
ETC has not yet been clearly defined. ET receptors are also found in
the nervous system where they may mediate neurotransmission. ET-1 has been
reported to participate in diverse biological activities, including local blood
flow regulation, cell growth, embryonic development, tissue remodeling,
inflammation, renal functions, pain, cardiovascular homeostasis, pulmonary
functions, and in the release of other active substances[3-6].
Whether ET-1 can penetrate through the blood–ocular barrier has yet to be
determined, although the susceptibility of the blood–brain barrier to ET-1 was
shown to differ between juveniles and adults in pathological conditions[7].
A few years
after ETs discovery, their roles in the eyes were reported by several other
research groups[8-10]. One such report revealed the production of
ET-1 by cultured bovine retinal endothelial cells and the presence of ET receptors
on associated pericytes[8]. Further, another report suggested ET-1
as a potential participant in the local regulation of intraocular pressure
(IOP), ocular blood vessel tone, and iris smooth muscle tone, suggesting that
it may be an important mediator in the development of ocular pathologic
conditions[9].
Subsequently,
many studies have been conducted regarding the role of ET-1 in ocular blood
flow, glaucomatous optic neuropathy (GON) with normal IOP, as well as in IOP
control and glaucoma with high IOP. However, this review will focus on the
former role, and will not address the latter.
ET-1
AND NORMAL-TENSION GLAUCOMA (NTG)
A few research groups, including our own, have reported that plasma
ET-1 levels may be associated with the pathogenesis of glaucoma, particularly
normal-tension glaucoma (NTG)[11-14]. We and Cellini et al
found that plasma ET-1 levels were significantly higher in patients with NTG
without systemic vascular or circulatory disorders than in normal controls[11,13].
We also demonstrated higher plasma ET-1 levels in NTG patients at the initial
stage of visual field loss than in those at the middle stage[11].
Kaiser et al found no physiological increase in ET-1 plasma levels in
NTG patients after changing from the supine to upright position, suggesting
that vascular dysfunction may be involved in the pathogenesis of optic nerve
damage in NTG[12]. A study using color Doppler imaging revealed
vascular insufficiency in NTG patients, particularly in the posterior ciliary
arteries that provide the blood supply to the optic nerve head (ONH)[13].
Another study indicated that resistivity index in the ophthalmic arteries was
positively related to plasma ET-1 levels[14].
Buckley et
al observed increased sensitivity to ET-1 in arteries dissected from the
gluteal fat of NTG patients, which could result in enhanced vasoconstriction
and contribute to the vasospasm seen in NTG[15]. In addition,
Nicolela et al demonstrated that glaucoma patients showed abnormally
high plasma ET-1 levels after the body cooled+. Recently, Terelak-Borys et
al provided evidence that abnormal neuro-endothelial function was related
to the effects of ET-1 via a vasospastic mechanism in NTG patients[17].
The ET-1-dependent vascular dysregulation known as Flammer syndrome[18] may be
one of the important causes of NTG. Moreover, Emre et al reported that
glaucoma patients (with either normal IOP or normalized IOP after treatment)
showing visual field progression had increased plasma ET-1 levels[19].
However, Chen et al found no correlation between plasma levels of ET-1
and the severity of glaucoma[20]. On the other hand, Lee et al
indicated that plasma ET-1 levels were associated with heart rate variability
in NTG patients, suggesting that the relationship between autonomic dysfunction
and autoregulation might play a role in the pathogenesis of NTG[21].
ET-1-INDUCED
MODELS OF GON
We and another research group independently reported
that ET-1 administration induced chronic ONH ischemia with enlarged excavation
of the ONH in animal eyes[22-25]. We injected ET-1 into the
posterior vitreous of rabbits twice a week for 4 weeks, which induced
continuous reduction in ONH blood flow and enlargement of the ONH excavation
(Figure 1) as well as axonal loss and demyelination affecting the prelaminar portion
of the optic nerve[22,25]. Cioffi et al also observed the ONH
excavation and histologic tissue loss in the anterior optic nerve resulting
from ischemia induced by ET-1-incorporated mini-pumps in rabbits and primates[23,24].
Stokely et al reported that intravenous ET-1 administration decreased
anterograde axonal transport in the rat optic nerve[26]. Prasanna et
al further indicated that ET-1 induced astroglial proliferation in cultured
human ONH astrocytes through ET receptor activation, suggesting a possible
mechanism for the astrogliosis observed in the glaucomatous ONH[27].
Lau et al provided experimental evidence that acute ET-1 injections
could produce retinal ganglion cell (RGC)-specific cell death and many cellular
changes that are similar to those observed in glaucoma[28].
Taniguchi et al revealed that a single intravitreous injection of ET-1
impaired retrograde axonal transport in the rat optic nerve, which was
correlated with the observed histological optic nerve damage[29].
These various findings suggest that ET-1-induced chronic ONH ischemia could be
a candidate model of GON. In fact, many researchers have evaluated
neuroprotection mechanisms for GON using this animal model[25,30-34].
Munemasa et al suggested that one of the glaucoma agents, unoprostone,
had neuroprotective effects against ET-1-induced neuronal injury through
phosphorylation of extracellular signal-regulated kinase. However, a majority
of the neuroprotective mechanisms have yet to be determined[33].
ET
RECEPTORS AND GON IN NTG
As described in the Introduction, ETA and ETB
receptors seem to be critical receptors for ET. ETA receptor plays
an important role in vasoconstriction. ETB receptors mediate both
vasodilation (ETB1) and vasoconstriction (ETB2), and some
of these effects are due to the release of other bioactive substances such as
nitric oxide, prostaglandins, and cytokines. Since ETB receptors are
clearance receptors for ET-1, their expression levels are important
determinants of the plasma ET-1 concentration[35].
Researchers in
Japan investigated whether gene polymorphisms of ET-1 and its receptors ETA
(EDNRA) and ETB (EDNRB) were associated with glaucoma
phenotypes and clinical features[36]. The GG genotype of EDNRA/C+70G
was associated with worse visual field defects in NTG patients, suggesting that
this polymorphism of the ETA receptor may be related to NTG risk.
Another study conducted in Korea also revealed that a polymorphism of the ETA
gene was associated with NTG[37]. Furthermore, a multi-center study
conducted in the United States revealed that EDNRB was associated with
early paracentral loss in glaucoma patients, suggesting that genes for the ETB
receptor may also be related with a certain type of glaucoma[38].
Henry et al
reported that NTG patients have reduced vasodilatation in response to ETA
receptor antagonism, which could be due to attenuated ETA
receptor-mediated tone and/or increased ETB receptor-mediated
contraction[39]. Resch et al indicated that dual inhibition
of ET receptors by bosentan increased ocular blood flow both in patients with
glaucoma and in healthy subjects[40]. On the other hand, we
suggested that ET-1 may act synergistically with glutamate to damage retinal
neurons under hypoxic conditions through ETA receptors[41].
In addition, we verified that ET-1 caused the death of retinal neurons through
activation of nitric oxide synthase and production of superoxide anions, which
were upregulated by ETA receptor-mediated activation of NADPH
oxidase[42,43]. Furthermore, Wang et al demonstrated the
immunoreactivity of ETB receptor in GON and its association with
astrocytes, suggesting that the glia-ET system may be involved in the
pathologic mechanisms of neuronal degeneration in glaucoma[44]. We
also reported that blocking the ETB receptors by the selective
antagonist BQ-788 rescued RGCs from optic nerve injury, most likely by
attenuating neuroinflammation[45]. In addition, Rao et al
reported that human lamina cribrosa (LC) cells expressed functional ETA
and ETB receptors, and their expression and function were altered in
response to prolonged exposure to ET-1, suggesting that elevated ET-1 levels
could impact LC function, including extracellular matrix (ECM) collagen
synthesis, and may contribute to ECM remodeling at the LC level in glaucoma[46,47].
Based on these findings, I summarize the probable involvement of ET-1 in the
pathophysiology of NTG as a schema in Figure 2.
ET
ANTAGONISTS FOR NEUROPROTECTION IN GLAUCOMA
There have been several reports that ET antagonists, particularly ETA
receptor antagonists, might be useful for neuroprotection in cerebral ischemic
injury[48-52]. The ETA receptor antagonist BQ-123
increased rat hippocampal CA1 neuron survival in gerbils subjected to transient
global ischemia[48]. The selective ETA receptor
antagonist Ro 61-1790 partially preserved tissue perfusion following focal
ischemia, and this effect was associated with significant neuroprotection in a
rat model of cerebral ischemia[49]. Another selective ETA
receptor antagonist, SB 234551, reduced neurological deficits in rat models of
closed head injury and focal stroke[50]. The ETA receptor
antagonist BSF-208075 reduced the post-ischemic leukocyte activation and showed
a neuroprotective effect[51]. Another specific ETA
receptor antagonist, S-0139, provided neuroprotection by suppressing ischemia-
and rtPA-triggered molecules in a rat model of middle cerebral artery occlusion[52].
On the other
hand, there have been few reports regarding the neuroprotective effects of ET
antagonists for glaucoma. Syed et al provided evidence that the
non-selective ET receptor antagonist sulfisoxazole could protect the retina
from ischemic-like insults similar to those occurring in glaucoma[53].
Howell et al showed that a novel, orally administered, dual ET receptor antagonist,
macitentan, inhibited neurodegeneration in a mouse model of glaucoma[54].
Therefore, considering the current knowledge on the potential involvement of
ET-1 in the pathogenesis of NTG, the use of a blockade of ET receptors may be
an attractive target for NTG treatment, although further studies are required
to confirm these effects and mechanisms. However, it should be noted that ET
antagonists might induce side effects, including hepatic dysfunction,
peripheral edema, and interstitial pneumonia, when applied systemically[55],
although the toxicity of their topical application remains to be verified. In
addition, ECE inhibitors might also be potential candidates for glaucoma
therapy, although their neuroprotective effects remain to be investigated.
CONCLUSION
In this article, the involvement of ET-1 and ET receptors in the
pathophyisiology of NTG was summarized, and the potential of the application of
ET antagonists for NTG treatment was discussed.
ACKNOWLEDGMENTS
I am grateful to my deceased
mentor, Professor Emeritus Ikuo Azuma. I would also like to express my
appreciation to Professor Tsunehiko Ikeda, Associate Professor Hidehiro Oku,
and other colleagues for their warm-hearted collaboration at the Department of Ophthalmology
in Osaka Medical College (Takatsuki, Osaka, Japan).
CONFLICT
OF INTERESTS
The author has no conflicts of
interest to declare.
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Peer reviewers: Petia Nikolova Kupenova, Associate Professor, Deptartmenet
of Physiology, Medical University-Sofia, 1 G Sofiiski St, 1431, Sofia,
Bulgaria; Alime Güneş, Department of Ophthalmology, Süleyman Demirel
University, Faculty of Medicine, The East Campus, Cünür, Isparta, 32260,
Turkey.
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