The angiogenic, neovascular proliferative
retinopathies, proliferative diabetic retinopathy (PDR), and
age-dependent macular degeneration (AMD) complicated by choroidal
neovascularization (CNV), also termed exudative or
“wet” AMD, are common causes of blindness. The
antidiabetic thiazolidinediones (TZDs), rosiglitazone, and
troglitazone are PPARγ agonists with demonstrable antiproliferative, and
anti-inflammatory effects, in vivo, were shown to ameliorate PDR
and CNV in rodent models, implying the potential efficacy of TZDs
for treating proliferative retinopathies in humans. Activation of
the angiotensin II type 1 receptor (AT1-R) propagates
proinflammatory and proliferative pathogenic determinants
underlying PDR and CNV. The antihypertensive dual AT1-R blocker
(ARB), telmisartan, recently was shown to activate PPARγ and improve glucose and
lipid metabolism and to clinically improve PDR and CNV in rodent
models. Therefore, the TZDs and telmisartan, clinically approved
antidiabetic and antihypertensive drugs, respectively, may be
efficacious for treating and attenuating PDR and CNV humans.
Clinical trials are needed to test these
possibilities.
1. Introduction
Angiogenesis and
neovascularization involve formation and proliferation of new blood vessels and
have a vital role normal growth and development, such as embryogenesis, wound
healing, tissue repair [1, 2]. However, in pathological neovascularization, angiogenesis
is aberrant and unregulated resulting in the formation of dysfunctional blood
vessels [3]. The latter occurs in proliferative diabetic retinopathy (PDR) and
choroidal neovascularization (CNV), “wet” or exudative age-dependent macular
degeneration (AMD), wherein pathological neovascular vessels proliferate and leak
fluid leading to retinal edema, subretinal and retinal/vitreous hemorrhage,
retinal detachment, and blindness. In the United States, PDR is the most
common preventable cause of blindness in adults <50 years [4], whereas CNV/AMD
is the leading cause of blindness among people of European origin >65 years
[5]. Both retinopathies are progressively destructive, leading to eventual and
irreversible blindness. PDR is a serious microvascular complication of both
type 1 and type 2 diabetes [6]. Type 2 diabetes is rapidly expanding worldwide
and is estimated to reach 380 million by 2025 [7, 8]. PDR is progressive and
compounded by persistent and substandard control of hyperglycemia, and concomitant
cardiovascular risk factors, especially hypertension [9–11]. Nearly, all type 1
diabetics and >60% of type 2 diabetics have significant retinopathy after
20 years, emphasizing the need for more cost-effective therapy [6, 10, 11]. Hyperglycemia,
advanced glycation end-products (AGEs), and hypoxia are believed to induce pathological
angiogenesis and neovascularization within the retina [12]. Prevention of
end-organ damage by early and aggressive diabetes management is the best
approach to treating diabetic retinopathy (DR) [6, 12].
Visual acuity
depends on a functional macula, located at the center of the retina where cone
photoreceptors are most abundant. Exudative (wet) AMD is complicated by CNV, involving
activation and migration of macrophages, and normally quiescent retinal pigment
epithelial cells from the choroid and invasion of defective neovascular blood
vessels into the subretinal space [13, 14]. Bleeding and lipid leakage from these
immature vessels damage the retina and lead to severe vision loss and blindness
[14, 15]. Current therapies of AMD are limited to treating the early stages of
the disease, and include laser photocoagulation, photodynamic therapy, surgical
macular translocation, and antiangiogenesis agents [13–16]. These invasive
procedures are expensive, require repetition, whereas pharmacologic approaches could
simplify therapy and reduce cost.
The peroxisome
proliferator-activated receptor (PPAR) class of nuclear receptors (PPARα, PPARβ/δ, and PPARγ)
belongs to the nuclear receptor superfamily that include the steroid, thyroid hormone,
vitamin D, and retinoid receptors [17, 18].
In 1995, Lehmann et al. [19] discovered that PPARγ was the intracellular
high affinity receptor for the insulin-sensitizing, antidiabetic thiazolidinediones
(TZDs), the activation of which also promotes growth arrest of preadipocytes,
differentiation, adipogenesis, and differentiation into mature adipocytes [20].
Ligand activation of PPARγ also downregulates the transcription of genes
encoding inflammatory molecules, inflammatory cytokines, growth factors,
proteolytic enzymes, adhesion molecules, chemotactic, and atherogenic factors [21–25]
(Table 1).
Growth factors, cytokines, chemokines, and
other proinflammatory mediators downregulated by PPARγ activation. PDGF-BB, platelet-derived
growth factor-BB homodimer; AP-1, activated protein-1; NF-κB = nuclear factor-κB;
NFAT = nuclear factor of activated T lymphocytes; STAT = signal transducer and
activator of transcription; ICAM, intracellular adhesion molecule; VCAM,
vascular cell adhesion molecule; iNOS, inducible nitric oxide synthase. (Adapted with permission from: B. Staels, "PPARγ and atherosclerosis." Current Medical Research and Opinion, vol. 21, Suppl. 1, pp. S13-S20, 2005; H. A. Pershadsingh, “Dual peroxisome proliferator-activated receptor-alpha/gamma agonists : in the treatment of type 2 diabetes mellitus and the metabolic syndrome.” Treatments in Endocrinology, vol. 5, no. 2, pp. 89-99, 2006.)
Growth factors
Cytokines
Chemokines
Nuclear transcription factors
Other molecules
ATII
IL-1β
IL-8
AP-1
IFN-γ
TGF-β
IL-2
MCP-1
NF-κB
iNOS
ET-1
IL-6
RANTES
STAT
PAI-1
bFGF
TNF-α
NFAT
MMP-2
PDGF-BB
MMP-9
EGF
VCAM-1
VEGF
ICAM-1
E-selectin
Angiotensin II (AII)
and components of the renin-angiotensin system (RAS) are expressed in the
retina [26, 27]. AII promotes retinal leukostasis by activating the angiotensin
type 1 receptor (AT1-R) pathway that propagates proinflammatory, proliferative
mediators (Table 2) leading to the development and progression of PDR [28–30]
and CNV [31]. By selectively blocking the AT1-R, angiotensin receptor blockers
(ARBs) or “sartans,” for example, valsartan and telmisartan have been shown to
confer neuroprotective and anti-inflammatory effects in animal models of retinal
angiogenesis and neovascularization [32–36]. Among the seven approved ARBs, telmisartan
and irbesartan were recently shown to constitute a unique subset of ARBs also
capable of activating PPARγ [37–39]. Valsartan and the remaining ARBs were
inactive in the PPARγ transactivation assay. In fact, telmisartan was shown to downregulate
AT1 receptors through activation of PPARγ [40]. Telmisartan was shown to provide
therapeutic benefits in rodent models of PDR [33, 41–44] and CNV [45] but data
with irbesartan is unavailable. Therefore, telmisartan and possibly irbesartan (data
unavailable) may have enhanced efficacy in treating proliferative
retinopathies. ARBs are safe and have beneficial cardiometabolic,
anti-inflammatory, and antiproliferative effects. Among these telmisartan and irbesartan may
have improved efficacy for targeting proliferative retinopathies. Table 3
provides relevant information on the various drugs described herein.
Growth factors, cytokines, chemokines, and
other proinflammatory mediators upregulated by angiotensin II stimulation. ET-1,
endothelin-1; TGF-β, transforming growth factor-β; CTGF, connective tissue
growth factor; bFGF, basic fibroblast growth factor; PDGF-AA, platelet-derived
growth factor-AA homodimer; EGF, epidermal growth factor; VEGF, vascular
endothelial cell growth factor; IL, interleukin; GM-CSF, granulocyte-macrophage
colony-stimulating factor; TNF-α, tumor necrosis factor-α; MCP-1, monocyte
chemoattractant protein-1; MIP, macrophage inflammatory protein; NF-κB, nuclear
factor-κB; NFAT, nuclear factor of activated T lymphocytes; STAT, signal transducer and activator of
transcription; RANTES, regulated on activation, normal T-cell expressed and
secreted; IFN-γ, interferon-γ; PAI-1, plasminogen activator inhibitor type 1;
AP-1, activated protein-1. (Adapted with permission from: R. E. Schmieder, K. F. Hilgers, M. P. Schlaich, B. M. Schmidt, “Renin-angiotensin system and cardiovascular risk.” Lancet, vol. 369, no. 9568, pp. 1208-1219, 2007.)
Growth factors
Cytokines
Chemokines
Other proinflammatory molecules
ET-1
IL-1β
IL-8
IFN-γ
TGF-β
IL-6
MCP-1
Tissue factor
CTGF
IL-18
MIP-1
PAI-1
bFGF
GM-CSF
RANTES
PDGF-AA
TNF-α
EGF
VEGF
Comparison of pharmacological and other
relevant properties of thiazolidinedione (TZD) full PPARγ agonists and dual angiotensin II type 1 receptor
blocker/selective PPARγ modulator (ARB/SPPARγM).
Parameter
TZDs†
ARBs*
Troglitazone
Pioglitazone
Rosiglitazone
Telmisartan
Irbesartan
Primary pharmacological target
PPARγ
PPARγ
PPARγ
AT1-R
AT1-R
Type of PPARγ agonists
Full PPARγ agonists
Selective PPARγ
modulator (SPPARγM)
Drug class (common names)
Thiazolidinedione (TZDs)
Angiotensin
receptor blockers (ARBs)
PPARγ activation (EC50inμM)
0.55
0.58
0.043
4.5
27
Therapeutic indication
Treatment of type 2 diabetes mellitus
Treatment
of hypertension
Primary therapeutic mechanism
Increase insulin sensitivity
Lower blood pressure
Serious adverse effect (Black box warning)
Fluid retention/weight gain/heart failure
None
None
Supplier/Pharmaceutical Co.
Sigma-Aldrich, St. Louis, Mo, USA
Takeda Pharmaceuticals North America, Deerfield, Ill, USA
GlaxoSmithKline, NC, USA
Boehringer- Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn, USA
Sanofi-Aventis, Bridgewater, NJ, USA
†Thiazolidinedione full PPARγ
agonists; troglitazone was withdrawn from the market (1998) because of association
with rare cases of fatal hepatic failure. Rosiglitazone and pioglitazone have
no such known association.
*Other FDA-approved ARBs had EC50 values >100μM (see [37, 38]). EC50 values shown were determined using the standard PPARγ-GAL4 transactivation assays.
2. Tissue Distribution PPARγ
Four PPARγ mRNA
isoforms have been identified [46] that encode two proteins, PPARγ1 and PPARγ2
[47, 48]. PPARγ1 is the principal subtype expressed in diverse tissues, whereas
PPARγ2 predominates in adipose tissue [49, 50]. The PPARγ2 protein differs from
PPARγ1 by the presence of 30 additional amino acids [49]. Tissue-specific
distribution of isoforms and the variability of isoform ratios raise the
possibility that isoform expression might be modulated by or reflect disease
states in which PPARγ activation or inactivation has a role. In humans, PPARγ
is most abundantly expressed mainly in white adipose tissue and large
intestine, and to a significant degree in kidney, heart, small intestine,
spleen, ovary, testis, liver, bone marrow, bladder, epithelial keratinocytes,
and to a lesser extent in skeletal muscle, pancreas, and brain [51].
2.1. PPARγ Expression in the Eye
PPARγ is
heterogeneously expressed in the mammalian eye [51–53]. PPARγ was found to be
most prominent in the retinal pigmented epithelium, photoreceptor outer
segments, choriocapillaris, choroidal endothelial cells, corneal epithelium,
and endothelium, and to a lesser extent, in the intraocular
muscles, retinal photoreceptor inner segments and outer plexiform layer,
and the iris [52]. Ligand-dependent activation of PPARγ evokes potent
inhibition of corneal angiogenesis and neovascularization [53–55]. The prominent expression of PPARγ in selected
tissues of the retina [52–54] provides the rationale for pharmacotherapeutic
targeting of PPARγ for treating ocular inflammation and proliferative
retinopathies [53–56].
2.2. Importance of PPARγ in Proliferative Retinopathy
To determine
whether endogenous PPARγ played a role in experimental DR, Muranaka et al. [54] evaluated retinal
leukostasis and retinal (vascular) leakage in streptozotocin-induced diabetic
C57BL/6 mice deficient in PPARγ expression (heterozygous genotype, PPARγ+/−)
after 120 days. Retinal leukostasis and leakage were greater (205% and 191%,
resp.) in the diabetic PPARγ+/− mice, compared
to diabetic wild-type (PPARγ+/+) mice. In streptozotocin-induced diabetic Brown
Norway rats, oral administration of the TZD PPARγ ligand, rosiglitazone for 21
days (3 mg/kg body weight/day, initiated post-streptozotocin injection) resulted
in suppression of retinal leukostasis by 60.9%(P<.05), and retinal
leakage by 60.8%(P<.05) [54]. Expression of the inflammatory
molecule. ICAM-1 protein was upregulated in the retina of the
rosiglitazone-treated group, though the levels of VEGF and TNF-α were
unaffected [54]. These findings provide
strong evidence for a role of PPARγ activity in the pathogenesis of DR and provide
novel genomic information that therapeutic targeting of PPARγ with a known
PPARγ ligand, the TZD rosiglitazone, can attenuate the progression of PDR. Whether a similar effect may apply to the
prevention or attenuation of CNV is currently unknown and should be explored.
3. Antidiabetic Thiazolidinediones (TZDs) and Proliferative Retinopathies
The
insulin-sensitizing TZDs, rosiglitazone, and pioglitazone are approved for the
treatment of type 2 diabetes. Because they increase target tissue sensitivity to
insulin without increasing insulin secretion [57], there is no risk of
hypoglycemia, though there is a risk fluid retention in diabetic patients,
especially those with coexisting heart failure, or at risk for developing CHF [58].
By activating PPARγ,
TZDs modulate groups of genes involved in energy metabolism [59], inflammation,
and cellular differentiation [60–64] by down-regulating the activity of the proinflammatory
nuclear receptors (NF-κB, AP-1, STAT, NFAT), and inhibiting the activity and
expression of inflammatory cytokines (TNF-α, IL-1β, IL-2, IL-6), iNOS, proteolytic
enzymes (MMP-3 and MMP-9), and growth factors (VEGF, PDGF-BB, bFGF, EGF, TGF-β)
(Table 1). Because of these broadly beneficial and protective actions of PPARγ
agonists, TZDs have been under development for the treatment of conditions
beyond type 2 diabetes, including atherosclerosis [64, 65], psoriasis [66],
inflammatory colitis [67], nonalcoholic steatohepatitis [68], and Alzheimer’s
disease [69]. More recently, TZDs have been found to protect against glutamate
cytotoxicity in retinal ganglia and have antioxidant properties [70] suggesting
that PPARγ agonists could prove valuable in targeting retinal complications [71].
3.1. Therapeutic Effects on Proliferative Diabetic Retinopathy (PDR)
Retinal
capillaries consist of endothelial cells, basement membrane neovascularization, and intramural
pericytes within the basement membrane which are important in vascular
development and maturation [44]. Selective loss of pericytes from the retinal
capillaries characteristically occurs early in diabetic retinopathy (DR) [72]. Diabetic macular edema (DME), often
associated with PDR, involves breakdown of the blood-retinal barrier and
leakage of plasma from blood vessels in the macula causing macular edema and
impaired vision [73, 74]. Resorption of the fluid from plasma leads to lipid
and lipoprotein deposition forming hard exudates [75]. In PDR, inflammation
leads to endothelial dysfunction, retinal vascular permeability, vascular
leakage, and adhesion of leukocytes to the retinal vasculature (leukostasis),
progressive capillary nonperfusion, and DME [12]. Intraretinal microvascular
abnormalities and progressive retinal ischemia lead to neovascular
proliferation within the retina, bleeding, vitreous hemorrhage, fibrosis, and
retinal detachment [74–76]. Despite advancements in ophthalmologic care and the
management of both type 1 and type 2 diabetes, PDR remains a leading cause of
preventable blindness [5–7]. Primary interventions, especially intensive
glycemic and blood pressure control, and management of other cardiovascular
risk factors are essential [6, 73–75]. Focal laser photocoagulation remains the
only surgical option for reducing significant visual loss in eyes with macular
edema [6, 9–12]. The risk of blindness with untreated PDR is currently greater
than 50% at 5 years, but can be reduced to less than 5% with appropriate
therapy [5–7]. At present, there is insufficient evidence for the efficacy or
safety of pharmacological interventions, including therapy targeting vascular
endothelial growth factor (i.e., anti-VEGF antibody therapy), though
intravitreal glucocorticoids may be considered when conventional treatments
have failed [6, 12].
Troglitazone and
rosiglitazone were shown to attenuate VEGF-induced retinal endothelial cell
proliferation, migration, tube formation, and signaling, in vitro [55] by
arresting the growth cycle of endothelial cells [62]. Local intrastromal
implantation of micropellets containing pioglitazone into rat corneas
significantly decreased the density of VEGF-induced angiogenesis, an accepted animal
model of retinal neovascularization [53].
Adverse conditions
that contribute to macular edema and retinal degeneration in PDR include
generation of advanced glycation end products (AGEs), local ischemia, oxidative
reactions, and hyperglycemia-induced toxicity [72, 75, 76]. In PPARγ-expressing
retinal endothelial cells, troglitazone, and rosiglitazone inhibited
VEGF-stimulated proliferation, migration, and tube formation [55, 77]. The
effects of troglitazone and rosiglitazone were also evaluated in the oxygen-induced
ischemia murine model of retinal neovascularization, an experimental model of
PDR [77]. Although the model lacks specific metabolic abnormalities found in
diabetes, it isolates the VEGF-driven process in which neovascularization is
stimulated by increased VEGF expression in the inner retina [77]. Both
troglitazone and rosiglitazone decreased the number of microvascular tufts
induced on the retinal surface, suggesting inhibition of an early aspect of
neovascularization. The inhibitory effects were dose-dependent (IC50≃5μmol/L) [77]. These findings
support the proposal that TZDs may have beneficial effects by reducing or
delaying the onset of PDR in diabetic patients. Prospective clinical trials are
required to demonstrate clinical efficacy.
3.2. Therapeutic Effects on Choroidal Neovascularization (CNV)
AMD complicated
with CNV involves angiogenesis and neovascularization in the choroid with hemorrhage
in the subretinal space, fluid accumulation beneath the photoreceptors within
the fovea, and neural cell death in the outer retina [13–16]. CNV is present with
vascular inflammation, unbridled vascular proliferation, aberrant epithelial
and endothelial cell migration, and inappropriate production of proinflammatory
cytokines, inducible nitric oxide synthase, growth factors, proteolytic
enzymes, adhesion molecules, chemotactic factors, atherogenic, and other
mediators that propagate defective blood vessel proliferation [5, 13–16, 78].
Elevated blood pressure, serum lipids, smoking, and insulin resistance also
have an etiological role in CNV development [78]. Therefore, control of cardiometabolic
risk factors is important in palliative management of CNV [79, 80]. Recently,
therapy for early exudative AMD has been directed toward intravitreal injection
of VEGF-directed antibodies or fragments thereof [14–16]. However, excessive cost
($1,950/dose) is a major issue [http://www.globalinsight.com/SDA/SDADetail6273.htm].
Monthly treatments are difficult for patients to tolerate, and the risk of
serious adverse effects increases over time [16]. On the other hand, synthetic,
nonpeptide PPARγ agonists [81, 82] are straightforward to synthesize, inexpensive
to formulate.
CNV comprises the
underlying pathology of exudative AMD, principally involving the subretinal
vasculature and choriocapillaris, leading to capillary closure and retinal
ischemia, angiogenesis, retinal neovascularization, bleeding into the vitreous,
retinal detachment and degeneration, and eventually vision loss [13–16]. PPARγ
is expressed in the choriocapillaris, choroidal endothelial cells, retinal
endothelial cells, and retinal pigmented epithelium [52, 83]. VEGF is a potent
inducer of retinal [13–16] angiogenesis and neovascularization. In their
landmark study, Murata et al. [83] demonstrated the expression of PPARγ1 in
human retinal pigment epithelial (RPE) cells and bovine choroidal endothelial
cells (CECs), and that application of the TZDs troglitazone or rosiglitazone
(0.1–20 μmol/L)
inhibited VEGF-induced proliferation and migration of RPE and CEC cells, and neovascularization [83]. Moreover, in the eyes of rat
and cynomolgus monkeys in which CNV was induced by laser photocoagulation,
intravitreal injection of troglitazone markedly inhibited CNV compared to
control eyes (P<.001). The treated lesions showed significantly
less fluorescein leakage and were histologically thinner in
troglitazone-treated animals, without adverse effects in the adjacent retina or
in control eyes [83]. These findings suggest that pharmacological activation of
PPARγ by TZDs appear to have a palliative or therapeutic effect on experimental
CNV. Again, clinical trials are required to demonstrate efficacy in the
clinical setting.
3.3. Adverse Effects of TZDs: Fluid Retention and Macular Edema
Pioglitazone and rosiglitazone
are generally safe though, in type 2 diabetic patients, there is a risk of
weight gain (1–3 kg) and fluid retention [58]. The incidence of
peripheral edema is greater in those concurrently taking exogenous insulin, increasing
from 3.0–7.5% to 14.7–15.3% [58]. The edema may be related to TZD-induced
vasodilation, increased plasma volume secondary to renal sodium reabsorption, and
reflex sympathetic activation [58]. The association of rosiglitazone treatment with
development of macular edema has been reported [84]. In a case review of 11
patients who developed peripheral and macular edema, while on the TZD therapy [85]
8 patients experienced resolution of macular edema with improved vision,
without laser treatment, 3 months to 2 years after TZD cessation. Therefore, DME
should be considered in type 2 diabetic patients treated with a TZD, especially
those with peripheral edema, or other symptoms or risk factors of CHF, or concurrently
taking exogenous insulin or nitrates.
Drug cessation usually results in rapid resolution of both peripheral
and macular edema [85].
4. Antihypertensive Angiotensin Receptor Blockers (ARBs) That Activate PPARγ
In their search
for PPARγ agonists that lack the adverse effects of TZDs, Benson et al. [37]
screened the active forms of all currently available antihypertensive “sartans”
(ARBs): losartan, valsartan eprosartan,
irbesartan, candesartan, telmisartan, and olmesartan, using the standard GAL-4
cell-based PPARγ transactivation assay. Only telmisartan and irbesartan [37, 38]
activated PPARγ and promoted adipogenesis, intracellular lipid accumulation and
differentiation of preadipocyte fibroblasts into mature adipocytes, in vitro, hallmark
properties of PPARγ agonists [19]. The EC50 values for transactivation
of PPARγ by telmisartan and irbesartan were 4.5 μmol/L and 27 μmol/L,
respectively [37–39] (Table 3). Although the PPARγ transactivation assay may
not recapitulate conditions in vivo, based on pharmacokinetic considerations,
concentrations of these ARBs required to activate PPARγ in vivo are achievable
by standard dosing [86, 87]. By functioning as partial PPARγ agonists this
unique subset of ARBs may provide added end-organ benefits in certain patient
populations such patients with the metabolic syndrome [87] and other
cardiometabolic risk factors, including atherosclerosis, atherogenesis, and may
have palliative effects on proliferative retinopathies.
ARBs bear an
acidic group (tetrazole or carboxyl group) at the ortho position on the terminal benzene ring of the biphenyl moiety,
which is essential for AT1 receptor binding. Telmisartan bears a carboxyl and
irbesartan, a tetrazole [87, 88]. The active forms of all other ARBs have two
acidic groups at opposite molecular poles. This second acidic group limits
accessibility, and hinders binding to the hydrophobic region of the PPARγ
receptor [87, 88]. Therefore, among currently available ARBs, the molecular
dipole appears to be an important structure-functional determinant of ligand
binding to the PPARγ receptor [87]. Compared to all other ARBs, telmisartan has
a uniquely long elimination half-life (24 hours), and the largest volume of
distribution (500 L, and >10-fold in excess of other ARBs) which greatly
increases central bioavailability upon oral dosing [86]. Furthermore,
telmisartan has been shown to have significant anti-inflammatory and
antioxidant activity, which may enhance its effectiveness in attenuating the
progression of proliferative retinopathies [89–91].
4.1. Full Versus Partial PPARγ Agonists
The PPARγ receptor
is composed of five different domains, an N-terminal region or domain A/B, a
DNA binding domain C (DBD), a hinge region (domain D), a ligand binding domain
E (LBD), and a domain F [81, 92, 93]. The A/B domain contains an activation
function-1 (AF-1) that operates in absence of ligand. The DBD confers DNA
binding specificity. PPARγ controls gene expression by binding to specific DNA
sequences or peroxisome proliferation-responsive elements (PPREs) in the
regulatory region of PPAR-responsive genes. The large LBD (∼1300Å3) allows the receptor to interact with a broad range of structurally distinct
natural and synthetic ligands [81, 92, 93]. The receptor protein contains 13
helices, and the activation function, AF-2 helix located in the C terminus of
the LBD is intimately integrated with the receptor's coactivator binding domain
[81]. Ligand-dependent stabilization is required for activation of the
downstream transcriptional machinery [81, 92, 93].
Thiazolidinedione full
agonists (TZDfa), for example, rosiglitazone and pioglitazone permit certain
coactivators to interact with the PPAR-LBD in an agonist-dependent manner and are
oriented by a “charge clamp” formed by residues within helix 3 and the AF-2 arm
of helix 12 in the LBD [45, 93]. Based on protease digest patterns and
crystallographic findings, the PPARγ non-TZD partial agonist (nTZDpa) [94] and
PPARγ partial agonist/antagonist, GW0072 [95] are mainly stabilized by
hydrophobic interactions with helixes H3 and H7.
The
antihypertensive ARBs telmisartan and irbesartan have been shown to function as
partial PPARγ agonists, similar to the previously identified nTZDpa [94]. Based on molecular motifs, telmisartan
appears to occupy a region in proximity with helix 3, with key interactions
between the carboxylic acid group of the ligand and Ser342 near the entrance of
the PPARγ pocket [37] (Figure 1). Telmisartan and irbesartan appear to cause an
alteration in the conformation of these helixes similar to that induced by nTZDpa
[37, 39], promoting differences in receptor activation and target gene
expression that confer a low adipogenic potential compared with full agonists
(TZDfa) like rosiglitazone and pioglitazone, which are known to have a high
adipogenic potential and promote weight gain [58, 81, 94]. Differential binding motifs reflecting full versus partial PPARγ
agonism are illustrated in Figure 2.
Telmisartan (blue)
superimposed on the co-crystal structure of GW0072 (red) bound within the PPARγ-LBD. Telmisartan and
GW0072 are Van der Waals space-filling representations, and the protein
backbone by the yellow ribbon. Formation of hydrogen bonds and interactions
between both ligands and the amide proton of Ser342 contribute toward
stabilization of the partial agonists within the PPARγ-LBD. (Kindly provided
by Dr. P.V. Desai & Professor M.A. Avery, Department of Medicinal
Chemistry, University of Mississippi, USA.)
Selective PPARγ modulator
(SPPARγM) model of PPARγ ligand action. PPARγ is a multivalent receptor whose ligand binding
domain can accommodate different PPARγ ligands. Ligands 1, 2, or 3 (e.g., full agonist, partial agonist, or
SPPARγM) are capable of
inducing distinct receptor combinations leading to selective gene expression.
Each ligand-receptor complex assumes a somewhat different three-dimensional
conformation, leading to unique and differential interactions with cofactors,
histones (acetylases/deacetylases), and other transcription factors.
Consequently, each PPARγ ligand-receptor
complex leads to a differential, but overlapping, pattern of gene expression.
Thus, each ligand will activate, or repress multiple genes leading to
differential overlapping expression of different sets of genes. (Adapted with permission from: J. M. Olefsky, “Treatment of insulin resistance with peroxisome proliferator-activated receptor gamma agonists.” Journal of Clinical Investigation, vol. 106, no. 4, pp. 467-472, 2000); H. A. Pershadsingh, “Treating the metabolic syndrome using angiotensin receptor antagonists that selectively modulate peroxisome proliferator-activated receptor-gamma.” International Journal of Biochemistry and Cellular Biology, vol. 38, nos 5-6, pp. 766-781, 2006.)
Several
coactivators, including CREB-binding protein complex, CBP/p300, steroid
receptor coactivator (SRC)-1, nuclear receptor corepressor (NcoR), DRIP204,
PPAR binding protein (PBP)/TRAP220, and PPARγ coactivator-1 (PGC-1), among
others, interface functionally between the nuclear receptor and the
transcription initiation machinery in ways not well understood [94].
Differential ligand-induced initiation of transcription is the consequence of
differential recruitment and release of selective coactivators and corepressors
[96] (Figure 3). For example, NcoR a silencing
mediator when bound to PPARγ suppresses adipogenesis in the absence of ligand. Activation
by TZDfa ligands causes release of NcoR and recruitment of the nuclear receptor
coactivator complex, NcoA/SRC-1 which promotes adipogenesis and lipid storage [94].
Schematic
diagram of the mechanisms of PPARγ action. In the unliganded state (top), the PPARγ
receptor exists as a heterodimer with the RXR nuclear receptor and the
heterodimer is located on a PPAR response element (PPRE) of a target gene. The
unliganded receptor heterodimer complex is associated with a multicomponent
corepressor complex, which physically interacts with the PPARγ receptor through
silencing mediator for retinoid and thyroid hormone receptors (SMRT). The
corepressor complex contains histone deacetylase (HDAC) activity, and the
deacetylated state of histone inhibits transcription. After PPARγ ligand
binding, the corepressor complex is dismissed, and a coactivator complex is
recruited to the heterodimer PPARγ receptor (bottom). The coactivator complex
contains histone acetylase activity, leading to chromatin remodeling,
facilitating active transcription. (Adapted with permission from: J. M. Olefsky, “Treatment of insulin resistance with peroxisome proliferator-activated receptor gamma agonists.” Journal of Clinical Investigation, vol. 106, no. 4, pp. 467-472, 2000); C. K. Glass, M. G. Rosenfeld, “The coregulator exchange in transcriptional functions of nuclear receptors”. Genes & Development,vol. 14, no. 2, pp. 121-141, 2000.)
Demonstration of
direct interaction between telmisartan or irbesartan with PPARγ protein, by
analyzing migration patterns of ligand-PPARγ protein fragments in trypsin
digestion experiments, indicated that both ARBs downregulated PPARγ mRNA and
protein expression in 3T3-L1 human adipocytes, a known property of PPARγ
ligands in adipocytes [39]. In fact, both telmisartan and irbesartan caused
release of NCoR and recruitment of NCoA/DRIP205 to PPARγ in a
concentration-dependent manner [39]. The transcription intermediary factor 2
(TIF-2), an adipogenic coactivator implicated in PPARγ-mediated lipid uptake
and storage, which increased the transcriptional activity of PPARγ, was
potentiated by pioglitazone but not by the ARBs [39]. Moreover, irbesartan and
telmisartan also induced PPARγ activity in an AT1R-deficient cell model
(PC12W), demonstrating that their effects on PPARγ activity were independent of
their AT1-R blocking actions [38]. These data demonstrate the functional relevance
of selective cofactor docking by the ARBs, and compared to pioglitazone,
identify telmisartan and irbesartan as unique selective PPARγ modulators
(SPPARγMs) that can retain the metabolic efficacy of PPARγ activation, while
reducing adverse effects, in parallel AT1-R blockade [37–39, 88]. Therefore, as
dual ARB/SPPARγM ligands, telmisartan and irbesartan have important
differential effects on PPARγ-dependent regulation of gene transcription,
without the limitations of fluid retention and weight gain, providing improved
therapeutic efficacy by combining potent antihypertensive, antidysmetabolic,
anti-inflammatory, and antiproliferative actions in the treatment of the
proliferative retinopathies.
4.2. Expression of the Renin-Angiotensin System in the Eye
The RAS evolved to
maintain volume homeostasis and blood pressure through vasoconstriction,
sympathetic activation, and salt and water retention [97]. AII binds and
activates two primary receptors, AT1-R, and AT2-R. In adult humans, activation
of the AT1-R dominates in pathological states, leading to hypertension,
atherosclerosis, cardiac failure, end-organ demise (e.g., nephropathy), and
proliferative retinopathies. AT2-R activation generally has beneficial effects,
counterbalancing the actions propagated through AT1-R. ARBs selectively block
AT1-R, leaving AII to interact with the relatively beneficial AT2-R. AII is
generated in cardiovascular, adipose, kidney, adrenal tissue, and the retina;
and through AT1-R activation promotes cell proliferation, migration,
inflammation, atherogenesis, and extracellular matrix formation [97].
AII and genes
enconding angiotensinogen, renin, and angiotensin converting enzyme (ACE) have
been identified in the human neural retina [98]. Prorenin and renin have been
identified in diabetic and nondiabetic vitreous, and intravitreal prorenin is
increased in PDR [99]. Angiotensin I and AII were found to be present in ocular
fluids of diabetic and nondiabetic patients [100]. AII and VEGF have been identified
in the vitreous fluid of patients with PDR [101], and AT1 and AT2 were
identified in the neural retina [102]. Furthermore, AT1 and AT2, AII, and its
bioactive metabolite Ang-(1–7) were identified in blood vessels, pericytes, and
neural (Müller) cells suggesting that these glial cells are able to produce and
process AII [102]. Thus, AII signaling via the AT1 pathway within the retina
may mediate autoregulation of neurovascular activity, and the onset and
severity of retino-vascular disease [103].
4.3. Pathophysiological Role of AT1 Activation in Proliferative Retinopathies
AT1 activation
participates in the pathogenesis of PDR, involving inflammation, oxidative
stress, cell hypertrophy and proliferation, angiogenesis, and fibrosis [101, 103].
The RAS is upregulated concomitant with hypoxia-induced retinal angiogenesis [102–104]
and is linked to AII-mediated induction of inflammatory mediators and growth
factors, including VEGF and PDGF [103–106]. AT1 blockade with candesartan
inhibited pathological retinopathy in spontaneously diabetic Torii rats by
reducing the accumulation of the advanced glycation end-product (AGE)
pentosidine [34]. AGEs contribute to vascular dysfunction by increasing the
activity of VEGF and reactive oxygen species [34]. Treatment with candesartan
reduced the accumulation pentosidine and VEGF gene expression in the diabetic
rat retina [34]. AT1-R, AT2-R, and AII were shown to be expressed in the
vascular endothelium of surgical samples from human CNV tissues and
chorioretinal tissues from mice in which CNV was laser-induced [40]. Therefore, the retinal RAS appears to have an
important pathophysiological role in proliferative retinopathies.
4.4. Therapeutic Effects of Telmisartan on PDR and CNV
AII
is among the most potent vasopressive hormones known and contributes to the
development of leukostasis in early diabetes [29]. Hypertension
increases retinal inflammation and exacerbates oxidative stress in experimental
DR [34, 107], and in diabetic hypertensive rats, prevention of hypertension
abrogaItes retinal inflammation and leukostasis in early DR [108]. Therefore,
RAS blockade by the dual ARB/PPARγ agonists, telmisartan or irbesartan, may
have enhanced effects for abrogating inflammatory and other pathological events
that contribute to or exacerbate PDR and CNV/AMD. In clinical studies,
reduction of hypertension by any means reduces the risk of development and the
progression of DR [109]. ARBs are widely used antihypertensive agents
clinically.
Induction of
diabetes by streptozotocin injection in C57BL/6 mice caused significant leukostasis
and increased retinal expression and production of AII, AT1-R, and AT2-R [30]. Intraperitoneal
administration of telmisartan inhibited diabetes and glucose-induced retinal
expression of ICAM-1 and VEGF, and upregulation of ICAM-1 and MCP-1, via
inhibition of nuclear translocation of NF-κB [33]. There have been no reports
on the effects of irbesartan on PDR or CNV/AMD.
In the
laser-induced mouse model of CNV, new vessels from the choroid invade the
subretinal space after photocoagulation, reflecting the choroidal inflammation
and neovascularization seen in human exudative AMD. Based a recent suggestion
[110], Nagai et al. [45] evaluated and compared the effects of telmisartan with
valsartan, an ARB lacking significant PPARγ activity [38, 39], and suitable
control to evaluate the role of telmisartan PPARγ activity. Both ARBs have identical
affinities for the AT1-R (∼10nmol/L) [97]. Telmisartan (5 mg/kg, i.p.) or
valsartan (10 mg/kg, i.p.) significantly suppressed CNV in mice [45]. Simultaneous
administration of the selective PPARγ antagonist GW9662, partially (22%) but
significantly reversed the suppression of CNV in the group receiving
telmisartan but not the group receiving valsartan [45], indicating separate beneficial
contributions via AT1 blockade and PPARγ activation, respectively [45]. Using
GW9662, similar findings were obtained identifying participation of PPARγ in
the suppressive effect of telmisartan on the inflammatory mediators, ICAM-1,
MCP-1, VEGFR-1 in b-End3 vascular endothelial cells, and VEGF and in RAW264.7
macrophages, unrelated to AT1 blockade [45]. These findings confirm that the
beneficial effects of telmisartan are derived from a combination of AT1
blockade and PPARγ activation. The inhibitory effects of valsartan were
insensitive to the presence of GW9662. This is the first known demonstration of
PPARγ-dependent inhibitory actions of a non-TZD PPARγ agonist on CNV. There
have been no reports on the effects of irbesartan on PDR or CNV.
4.5. Therapeutic Potential of Dual ARB/SPPARγMs
Reduction in the
cardiometabolic risk profile by lowering high blood pressure, improving insulin
sensitivity, normalizing the lipid profile, and inhibiting inflammatory pathways
are known to impede the pathological evolution of proliferative retinopathies. The dual ARB/SPPARγM ligands, telmisartan
has been shown to be effective in this regard in the rodent model, though
irbesartan has yet to be tested experimentally. PPARγ activation has beneficial
effects by lowering hyperglycemia and improving the metabolic profile in
individuals with type 2 diabetes and the metabolic syndrome. The fact that both
AT1-R blockade and PPARγ activation by telmisartan had independent synergistic
effects in the murine model of laser-induced CNV is an important finding [40]. It
would be useful to test whether irbesartan has effects similar to those of telmisartan
in animal models of PDR and CNV/AMD [28, 31–34, 40], as both ARBs similarly attenuate
inflammation, proliferation, and improve the metabolic syndrome [111, 112]. Also,
unlike TZDs, telmisartan (but not valsartan) increases caloric expenditure and
protects against weight gain and hepatic steatosis [113]. With its high lipid
solubility, large volume of distribution, and other favorable pharmacokinetic
properties [86–88], telmisartan may be effective when administered orally. If oral
delivery proves therapeutically ineffective, the drug may be formulated for administration
via implant or transscleral application for local delivery to the posterior
segment [114–116].
5. Concluding Remarks
Hypertension,
insulin resistance, dyslipidemia, and risk for atherosclerosis and atherogenesis,
all components of the metabolic syndrome, comprise significant epidemiologic
risk factors for neovascular, proliferative retinopathies [6, 9, 12, 117, 118]. Photodynamic and anti-VEGF therapy, current
treatments for CNV/AMD are cost-intensive. Treatments for PDR are limited to
surgical options in advanced disease when the visual function is irreversibly
affected [3–6, 14, 15, 16]. Therefore, alternative, low cost, prophylactic and/or
palliative pharmacotherapeutic approaches are attractive and desirable. The currently approved antidiabetic TZD, rosiglitazone (a full PPARγ agonist), and the antihypertensive ARB, telmisartan (a partial PPARγ agonist) have both shown promise in animal models of proliferative retinopathies. The potential efficacies of irbesartan in
proliferative retinopathies remain to be determined. Administration of TZDs
may, in patients with AMD, slow the progression to CNV, and in patients with
diabetic retinopathy attenuate the progress to PDR, provided that: (1) their
risk of macular edema is low, (2) they lack symptoms of CHF or cardiomyopathy,
and (3) are not taking insulin or nitrates. The efficacy and safety limitations
of the TZDs are well understood [119–123] and their use would require careful
benefit-to-risk analysis. Because these drugs have been in use clinically for a
decade, well-designed retrospective analyses in carefully selected patient populations
may reveal useful information regarding their clinical potential.
Several SPPARγMs currently which are under development for treating type 2 diabetes [124] could be screened in animal models of PDR and CNV to determine their potential efficacy for treating proliferative retinopathies. Long-term,
prospective clinical trials are needed to demonstrate the efficacy of currently
approved TZDs and ARBs (Table 3). Notably, three large prospective phase III
trials are underway to evaluate the effect of the ARB, candesartan on retinopathy
in normotensive type 1 and type 2 diabetes patients, the diabetic REtinopathy candesartan
trials (DIRECTs) Programme [125]; estimated study completion date: June 2008.
These studies will provide important insight into the potential efficacy of ARBs
in general in the treatment of DR. With their capacity for activating PPARγ and
improving the metabolic profile, the clinical efficacy of telmisartan and possibly
irbesartan could be evaluated in patients at risk for developing PDR and CNV, especially
those with deficiencies in carbohydrate and lipid metabolism. Moreover, with
their unique structure/activity profile, these compounds may provide a drug discovery
platform for designing therapeutic agents for treating proliferative retinopathies.
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