# PPARδ Activity in Cardiovascular Diseases: A Potential Pharmacological Target

Authors: Angela Tesse; Ramaroson Andriantsitohaina; Thierry Ragot
Journal: PPAR Research
 (2009)

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## Abstract

Activation of peroxisome proliferator-activated receptors (PPARs), and particularly of
PPARα and PPARγ, using selective agonists, is currently used in the treatment of metabolic diseases such as hypertriglyceridemia and type 2 diabetes mellitus. PPARα and PPARγ anti-inflammatory, antiproliferative and antiangiogenic properties in cardiovascular cells were
extensively clarified in a variety of in vitro and in vivo models. In contrast, the role of PPARδ in cardiovascular system is poorly understood. Prostacyclin, the predominant prostanoid released by
vascular cells, is a putative endogenous agonist for PPARδ, but only recently PPARδ selective synthetic agonists were found, improving studies about the physiological and pathophysiological roles of PPARδ activation. Recent reports suggest that the PPARδ activation may play a pivotal role to
regulate inflammation, apoptosis, and cell proliferation, suggesting that this transcriptional factor could become an interesting pharmacological target to regulate cardiovascular cell apoptosis, proliferation, inflammation, and metabolism.


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## Body

## 1. Introduction

Peroxisome proliferator  activated receptors (PPARs) are transcriptional factors of intense
interest through their involvement in several biological processes such as energy
homeostasis, cell proliferation and differentiation, fatty acid catabolism, and
adipogenesis [1]. Among the three PPAR isotypes identified, PPARα and PPARγ had been the most extensively studied. PPARα is activated by several fatty acids and
expressed in tissues exhibiting a high rate of fatty acid catabolism (liver,
heart, kidney, and muscle). In the cardiovascular system, PPARα is expressed in
cardiac and smooth muscle cells, in endothelial cells and monocyte/macrophage
cells [2, 3], and it regulates fatty acid transport, esterification, and
oxidation, via activation of genes encoding key enzymes involved in these
processes [4]. We have also previously described that the PPARα gene deletion
induced defects of the cardiac contractile performance and myocardial fibrosis,
suggesting a major role of PPARα in the maintenance of cardiovascular
homeostasis within the physiological range [5].PPARγ
is the most studied PPAR subtype, and is primarily expressed in adipose tissue
where it participates in the transcription of various genes involved in lipid
metabolism, glucose homeostasis regulation, and in the inflammatory processes,
preventing foam cell formation [6] and reducing nitric oxide (NO)
overproduction, interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α)
expressions. PPARγ activation suppresses cyclo-oxygenase-2 (COX-2)- and inducible
nitric oxide synthase (iNOS)-inductions by repression of NF-κB and AP-1 [7, 8].
PPARγ can
be activated by synthetic agonists of the thiazolidinedione family, for
instance, rosiglitazone (RZ) [9], which is able to reduce the inflammatory
markers in diabetic patients [10]. Several studies have shown that some effects
of PPARγ agonists are PPARγ-independent [11, 12]. In contrast, we have recently
found a direct PPARγ-dependent
protective action of RZ on vascular dysfunction accompanying smooth
muscle cell inflammation. Indeed, selective PPARγ inhibitor, GW9662, completely abolished the
beneficial anti-inflammatory effects of RZ [13].PPARδ
(also known as PPARβ and NR1C2) is the most ubiquitously expressed, although
its physiological and pathological roles are unclear, especially in human
tissues [14, 15]. Prostacyclin, the predominant prostanoid released by vascular
cells, is a putative endogenous agonist for PPARδ [16, 17]. The roles of PPARα
and PPARγ in vascular cells were extensively investigated in a variety of in
vitro and in vivo models, both having in general anti-inflammatory and antiproliferative
properties [18]. In contrast, the role of PPARδ in cardiovascular functions is
not fully understood but there is a rising interest for this nuclear receptor
in this domain because of its pivotal role in apoptosis and cell proliferation
[19–21], and for its function as a key regulator of fatty acid metabolism [22, 23]. On the light of the recent data, in the present review, we focused our
attention on the new therapeutic approaches, using selective agonists of PPARδ,
to regulate cardiovascular function and cardiac and vascular cell
proliferations and apoptosis in several cardiovascular pathologies.


## 2. PPARδ Agonists

Like
other PPAR subtypes, PPARδ is activated by a large variety of endogenous
agonists, such as lipids, including long-chain dietary fatty acids [23], and
prostacyclin (PGI2) [16, 17]. Synthetic analogs of PGI2,
such as carbaprostacyclin (cPGI2), are able to bind to and to act as
agonists of PPARδ. PPARα and PPARδ possess overlapping ligand specificities,
thus, fatty acids and PGI2 analogs have been shown to induce transcriptional
activation and DNA binding of both PPAR subtypes [24]. Moreover, stable
prostacyclin analogs are able to activate in vitro also PPARγ in a cell
surface prostacyclin receptor-dependent manner [25].Moreover,
several high-affinity synthetic PPARδ ligands were identified and have
contributed to improve studies about the physiological and pathophysiological
roles of PPARδ activation. These PPARδ activators include the phenoxyacetic
acid derivatives GW501516 and GW0742 (GlaxoSmithKline, Brentford, UK) [26], and
L165041 (Merck, Whitehouse Station, NJ, USA) [27]. GW501516 and GW0742 agonists
show a thousand-fold PPARδ selectivity over other PPAR subtypes [26] while
L165041 has a weak PPARγ
binding activity at concentrations higher than 5 μM [27].
The PPARδ
agonists have different bioavailability and effects in the lipoprotein delivery
system according to animal models, primate, or mouse for instance [28]. There
are also two other synthetic agonists with high affinity for both PPARγ and
PPARδ: L796449 and L165461 [27]. Now, several new synthetic PPARδ agonists are
in development for clinical applications: MBX-8025 (Metabolex Inc, Calif, USA),
CER-002 (Cerenis Therapeutics, Mich, USA), and KD3010 (Kalypsys, Calif, USA)
[29].


## 3. Role of PPARδ in Cell Apoptosis and Cell Proliferation

Several
reports showed that PPARδ activation by PGI2, its analogues, or selective
ligands, acutely regulates endothelial cell apoptosis and protects endothelial
cells from apoptosis caused by oxidant stress [30], or induces human umbilical
endothelial cell (HUVEC) proliferation [19]. PPARδ activity is also involved in
a negative control of colorectal cancer and keratinocyte cell apoptosis [31, 32]. Synthetic PGI2 has been shown to protect renal cells from
hypertonicity-induced apoptosis, which was attributed to PPARδ activation [33].
More recently, it was found that endothelial cell survival was improved in
HUVECs transduced with an adenovirus containing genes that selectively increased
PGI2 synthesis [30]. The authors revealed, for the first time, that
PGI2 upregulates 14-3-3ε promoter activity in a PPARδ-dependent
manner. Indeed, 14-3-3ε upregulation leads to increase of BAD binding and decreasing of BAD translocation to mitochondria with
subsequent inhibition of cytochrome c release, caspase-3 activation and endothelial cell hydrogen
peroxide (H2O2)-induced apoptosis [30]. Furthermore, the
PPARδ overexpression amplifies the antiapoptotic action of PGI2.
More recently, the mechanisms by which PPARδ agonists control the 14-3-3ε
expression were investigated and it was suggested a key anti-inflammatory role
of PPARδ activation in promoting endothelial cell survival [34].It
is known that reactive oxygen species (ROS), mediators of oxidative stress,
play a deleterious role on vasculature and myocardium. ROS and H2O2 have been reported to induce apoptosis in various cell types. The role of
PPARδ activation using GW501516 was also investigated in H2O2-induced
apoptosis in rat cardiomyoblasts. PPARδ exerts an antioxidant role in rat
cardiac myoblasts by increasing catalase expression in presence of H2O2 with a subsequent cell protection from H2O2-induced
apoptosis that is caspase-3-dependent [35].Concerning
the cardiac injury and cardiomyocyte death induced by ischemia, a recent study
provides several lines of evidence indicating a cardioprotective effect of
GW0742, via upregulation of survival signalling and suppression of apoptotic
cell death. Indeed, GW0742 is able to reverse the detrimental effect of
ischemia/reperfusion on expression of Bcl family genes. This reduces expression
of proapoptotic genes, Bax and Bid, and reverses the ischemia-dependent downregulation
of the antiapoptotic gene, Bcl-xL [36]. Moreover, GW0742 treatment reduces the
ischemia/reperfusion-induced cardiac mitochondrial damage that is a critical
step in cell apoptotic death controlled by Bcl family proteins. Activation of
PPARδ by this agonist also reduces the myocardial caspase-3 activity and increases cardiac p-Akt and
its upstream regulator, p-PDK, a central kinase for signalling pathway
regulating cell survival and cell growth [37].The
role of PPARδ activation in cell proliferation is somewhat controversial. Cardiac
fibroblast proliferation, differentiation of fibroblasts to myofibroblasts, and
collagen synthesis were reduced after PPARδ activation [37]. It was shown that
a prostacyclin agonist, the beraprost sodium, is able to enhance the PPARδ and
iNOS expressions with an antiproliferative effect in rat aortic smooth muscle
cells, suggesting that iNOS is a downstream target of PPARδ [38]. Moreover,
suppression of PPARδ expression by RNAi targeting significantly promoted the
proliferation of human colorectal cancer cells (HCT-116) by increasing the
number of cells in G1 phase [39]. In contrast, in another work, Zeng et al. have shown that PPARδ is able to induce cell proliferation in human thyroid
tumors by regulating epithelial cell proliferation via cyclin E1, growth factor
and lipid signals. Moreover, PPARδ is upregulated
in human thyroid tumors and the deregulation of the PPARδ/cyclin E1 pathway may
be important not only in thyroid cancer but also in other types of carcinomas
[40]. PPARδ expression and activation were rapidly stimulated by epidermal
growth factor (EGF) stimuli in HaCaT keratinocytes and this promoted cell
proliferation [41]. PPARδ-/- mice exhibit increased keratinocyte proliferation when
treated with a tumor promoter [42]. On the light of these new studies, the
effects of PPARδ activation on cell proliferation seem to be cell type specific.
PPARδ roles in apoptosis and cell proliferation are synthesized in Figure 1.Figure 1
Effects of PPARδ activation on potential targets implicated in cell death,
cell proliferation, and inflammation. PPARδ can be activated not selectively by endogenous agonists (EAs), such as several
lipids, long-chain fatty acids (LCFAs), and prostacyclin (PGI2), or
synthetic agonists (SAs). PPARδ activation has an antiapoptotic effect reducing
reactive oxygen species (ROS), upregulating 14-3-3ε activity and reducing
cytochrome c release from mitochondria and subsequent caspase-3 activation. The
effect of PPARδ activation on cell proliferation is cell type dependent. It has
a proangiogenetic effect in human umbilical endothelial cells (HUVECs), a proproliferative
effect in keratinocytes (KCs), while an antiproliferative effect in smooth
muscle cells (SMCs) and in cardiac fibroblasts (FBs) with subsequent reduction
of heart fibrosis. PPARδ activation in endothelial progenitor cells (EPCs)
enhances vasculogenesis. PPARδ has anti-inflammatory effects by reducing
cytokines production and molecules implicated in endothelial/leukocyte
interactions.


## 4. PPARδ in Angiogenesis and Vasculogenesis

PPARδ
activation could play an important role also in vascular growth, in particular
in vasculogenesis from endothelial progenitor cells (EPCs) and angiogenesis
deriving from pre-existing endothelial cells [43]. A recent study showed that
PPARδ activation, using GW501516, induces cell proliferation in human
endothelial cell cultures and angiogenesis in a murine Matrigel plug assay in vivo through a mechanism that
involves vascular endothelium growth factor (VEGF) gene transcription.
Moreover, the same study showed that GW501516 is able to induce transcription
of PPARδ target genes such as the adipose differentiation-related protein
(ADRP), VEGF, and the matrix metalloproteinase-9. These data suggest that
endogenous prostacyclin, like the synthetic agonist GW501516, may regulate
endothelial cell proliferation and angiogenesis through a PPARδ-dependent VEGF
gene expression [19].PPARδ
activation with agonists, GW501516 or L-165041, increased the proliferation of
human early EPCs and protected them from hypoxia-induced apoptosis. In
addition, PPARδ activation enhanced EPC transendothelial migration and tube
formation [44]. Injection of the GW501516-treated human or mouse early EPCs, in
a hind limb ischemia model of athymic nude mice,
significantly accelerated limb perfusion improvement after 21 days of ischemia. This was associated with an increased capillary density determined by
histological studies. PPARδ agonist-treated EPCs from
PPAR-δ-/- mice failed to
enhance vasculogenesis. These findings suggest that ex vivo activation of PPARδ
in early EPCs results in enhanced vasculogenic potential in vivo, and this was
confirmed also in a corneal neovascularization model [43]. The beneficial
effects observed after PPARδ activation in EPCs are mediated by the PIK/Akt
pathway implicated in vasculogenesis [45–47]. More recently, He and coworkers
provided evidences that the proangiogenic effects of human late EPCs are
partially dependent on biosynthesis and release of PGI2 and
subsequent PPARδ activation [48]. Indeed, in the same study, the downregulation
of PPARδ expression impaired in vivo angiogenesis in nude mice transplanted
with EPCs, treated with COX-1 or PGI2 synthase (PGIS) small
interfering RNAs, supporting the concept that the COX-1/PGI2/PPARδ
pathway in human EPCs plays an important role in angiogenesis [48].Interestingly, a tumor vascularization defect was
found in PPARδ-/- mice with subsequent decreased progression and partial
regression of tumors in this mouse model. This was due to the abundance of
highly abnormal hyperplastic microvessels appearing dysfunctional in tumors
from PPARδ-/- mice [49]. Even though a defect in angiogenesis has not been
observed during normal development of PPARδ-/- mice, PPARδ is specifically
required by tumor endothelial cells to orchestrate their proliferation and
differentiation in an environment providing abnormal sources of growth factors
and cytokines [49]. These findings suggest an interesting potential for
clinical applications of PPARδ as a target in the tumor treatment.


## 5. Role of PPARδ in Atherosclerosis

The
atheroprotective role of PPARδ activation remains controversial. The PPARδ
activation using GW0742 reduces only weakly atherosclerosis formation in mice
knockout for the low-density lipoprotein receptor (LDLR) gene [50]. In another
study, administration of the same agonist at a lower dose failed to have an
effect in foam cell formation and in vascular lesions in the same mouse model
[51]. The limited atheroprotective effect of GW0742 might be explained through
its inability to modify high-density lipoprotein cholesterol (HDL-c) levels in
both studies.Besides, more recently, it was confirmed a vascular protective
effect of PPARδ activation in a model of angiotensin II (Ang II)-induced
atherosclerosis in LDLR-/- mice. The authors evidenced attenuated Ang
II-accelerated atherosclerosis through the increased expression of the
anti-inflammatory corepressor, B cell lymphoma-6 (Bcl-6). Furthermore, Ang II
activation of MAP kinases (p38 and ERK1/2) was inhibited in LDLR-/- mice
infused with Ang II and treated with a high-fat diet supplemented with GW0742
[52]. Another selective PPARδ agonist, GW501516, has been reported to reduce
atherosclerotic lesion formation in ApoE-/- mice submitted to high-fat diet
[53]. This agonist was able to improve HDL-c blood levels in these mice in
agreement with results previously obtained in monkeys [54]. Indeed, GW501516
promotes reverse cholesterol transport in macrophages, a key step in reducing
foam cell formation, by increasing expression of the reverse cholesterol
ATP-binding cassette transporter A1. This agonist also causes a dramatic dose-dependent
rise of HDL-c, while it decreases the levels of LDLs in serum of obese Rhesus
monkeys [54]. PPARδ agonists may also possess antiatherosclerotic properties in
vivo by decreasing the amount of nonliganded PPARδ receptor and by releasing
the transcriptional repressor Bcl-6 of foam cells [55]. Furthermore, in the
work of Barish et al. [53], DNA array and real-time PCR analyses, conducted in
aortas from GW501516-treated ApoE-/- mice, have evidenced potential PPARδ
target genes. Experiences have shown a downregulation of both CXCL7 and CCL21α,
implicated in neutrophil and T lymphocyte recruitment induction. In contrast,
others proteins were upregulated, in particular the regulators of G protein
signalling (RGS) 4 and 5, which antagonize the signalling mediated by the chemokine
receptors. The tissue inhibitor of metalloproteinase 3 (TIMP3), implicated in
smooth muscle cell migration and lesion stability, was also upregulated. At
last, chemokine expression was downregulated by GW501516, confirming the
anti-inflammatory property of PPARδ activation [53].Endothelial
cell monolayer is exposed to circulating inflammatory factors that predispose
to atherosclerosis. Increasing evidences suggest that the endothelial cell
apoptosis might contribute to the development of atherosclerosis and acute
coronary syndromes [55]. PPARδ agonists might modulate the development of
atherosclerosis and acute coronary syndrome, not only by targeting foam cells
and lipoprotein metabolism [56, 57], or protecting against obesity [58], but
also by promoting endothelial cell survival via 14-3-3ε [34]. Indeed, 14-3-3
and 14-3-3ε proteins are antiapoptotic and anti-inflammatory molecules in
endothelial cells and they may play an important role in atherothrombosis [30, 59, 60]. In particular, 14-3-3 proteins modulate crucial aspects of heart
function both in and in vivo [60–63]. In a recent study, GW0742
and GW501516 significantly inhibit the vascular cell adhesion molecule 1
(VCAM-1) and E-selectin expressions induced by TNFα, ensuing in reduced endothelial-leukocyte
adhesion in HUVECs. Moreover, PPARδ activation upregulates expression of antioxidative
genes such as superoxide dismutase 1, catalase, and thioredoxin, leading to a
reduced ROS production in endothelial cells [64]. These studies suggest the
protective role played by PPARδ in the regulation of multiple proinflammatory
pathways with subsequent atherosclerosis suppression.


## 6. Role of PPARδ in Cardiac Protection

PPARδ
is the predominant PPAR subtype in cardiac cells and it is implicated in the
regulation of cardiac lipid metabolism, suggesting its important role in
cardiac diseases. Indeed, mice with cardiac-specific deletion of the PPARδ gene
developed myocardial lipid accumulation and cardiomyopathy [65].The
inflammatory response following cardiac ischemia/reperfusion is a determinant
factor responsible for tissue injury development triggered by the cytokine
cascade and the upregulation of adhesion molecules and chemokines. These events
enhanced neutrophil and monocyte infiltrations into myocardium and lead to
cardiac damage [66]. The PPARδ activation by GW0742 reduces inflammatory
cytokine expression, ending up in a reduction of plasma levels of some interleukins
(IL-6 and IL-8). Furthermore, GW0742 is able to decrease expression of the
adhesion molecule for leukocytes, ICAM-1, and of the chemokine responsible for
monocyte recruitment, MCP-1, in a cardiac ischemia/reperfusion model [36].Diabetes
predisposes to heart failure, particularly in combination with other comorbid
conditions such as hypertension and coronary artery disease [67]. The incidence
of heart failure and death, following myocardial infarction, is higher in
diabetic than in nondiabetic individuals [68]. PPARα and PPARδ drive distinct
cardiac metabolic regulatory programs in mouse models of type 2 diabetes.
Indeed, PPARδ activates, whereas PPARα represses, targets involved in the
cellular glucose utilization, resulting in reciprocal effects on cellular
glucose uptake through differential regulation of glucose transporter 4
(GLU4/SLC2A4) transcription. These findings suggest that cardiac specific
overexpression of PPARδ is cardioprotective in diabetes [22].The
development of heart failure is also associated with extensive fibrosis, which
aggravates diastolic dysfunction and predisposes to arrhythmias [69, 70]. A
critical event in fibrosis initiation is the proliferation and differentiation
of cardiac fibroblasts. Upon activation by cytokines, growth factors, or
stretch, fibroblasts start their proliferation and ultimately differentiate
towards myofibroblasts, acquiring smooth muscle-like properties [71, 72].
Although fibroblasts take care of normal collagen turnover [73], myofibroblasts
are rather responsible for the alteration of extracellular matrix accumulation,
often leading to impaired organ function [54]. PPARδ activation leads to
reduced cardiac fibroblast proliferation by a mechanism that involves the upregulation
of PPAR-responsive cell cycle inhibitory G0S2 gene [37]. Moreover, heart
collagen is inhibited after PPARδ activation. These findings are in agreement
with another work, in which it was found a protective effect of PPARδ
activation by GW501516 in the inhibition of Ang II-induced collagen type I
expression via a decreased collagen synthesis in adult rat cardiac fibroblasts
[74].In
the transitions from foetal to neonatal and to adult life, cardiac metabolism
switches from glucose to fatty acids as a preferred energetic substrate to
generate ATP [75]. In contrast, cardiac hypertrophy is associated with an
increase in glucose utilization and a decrease in fatty acid oxidation [76]. It
was found that the PPARδ activation by L-165041 inhibits the
phenylephrine-induced hypertrophy in neonatal rat cardiac myocytes. The target
is NF-κB signalling pathway that plays a pivotal role in the hypertrophic
response of cultured cardiac myocytes [77]. Moreover, hypertrophy in neonatal
rat cardiomyocytes caused a reduction in expression of pyruvate dehydrogenase
kinase 4 (Pdk4), a target gene of PPARδ involved in fatty acid
utilization.  Indeed, NF-κB activation, during cardiac hypertrophy, downregulates
PPARδ activity, leading to a fall in fatty acid oxidation, through a mechanism
that involves enhanced protein-protein interactions between the p65 subunit of
NF-κB and PPARδ and a subsequent reduction on expression of PPARδ target genes
[23]. On the basis of the literature, one can think that several therapeutic
approaches using PPARδ agonists may be possible to treat vascular and cardiac
pathological states, especially those in which inflammation, fibrosis, and
lipid metabolic disorders are involved. The effects of PPARδ activation on
cardiac cells are synthesized in Figure 1.


## 7. Role of PPARδ Activation in Metabolic Diseases

High-fat
diet, a sedentary way of life, and genetic factors seem to account for the
development of cardiovascular diseases, including atherosclerosis and heart
stroke. At the same time, obesity is an important risk factor for
cardiovascular disorders, since it is often associated with hypertension and
increases the risk of metabolic disorders such as insulin resistance, hypertriglyceridemia
and low plasmatic levels of HDL-c. Patients characterized by these metabolic
abnormalities may be considered as affected by the metabolic syndrome. PPARδ is
involved in lipid metabolism control and energy homeostasis [78]. The PPARδ
activation promotes fatty acid catabolism in several tissues, such as skeletal
muscles and adipose tissue [57, 79]. Moreover, several recent studies suggest a
potential role of PPARδ in the regulation of glucose metabolism and insulin
sensitivity [80]. PPARδ agonists have advantageous effects in obesity
prevention and modulation of lipoprotein metabolism [54, 57, 58]. Indeed,
transgenic mice overexpressing PPARδ are protected against diet-induced obesity
through an increased catabolism of fatty acids [58]. Moreover, administration
of PPARδ agonists to mice treated with a high-fat diet decreased insulin
resistance by enhancing fatty acid oxidation and decreasing lipid content of
skeletal muscles [57].Pharmacological
activation of PPARδ, using GW0742, protects heart from ischemia/reperfusion
injury in male Zucker fatty rats, a rodent model of obesity and dyslipidemia
[36]. All these studies suggest a protective effect of PPARδ activation in the
cardiovascular complications induced by metabolic disorders.


## 8. Conclusion

PPARδ activation is presently used as a new
therapeutic approach in several metabolic and cardiovascular pathological
states. PPARδ activators are in development for the treatment of dyslipidemia,
obesity and/or insulin resistance in patients with the metabolic syndrome [78].
PPARδ agonists have advantageous effects in obesity prevention and modulation
of lipoprotein metabolism [54, 57, 58]. GW501516 was tested for its effects on
dyslipidemia in obese Rhesus monkeys. This agonist increased of 79% HDL-c and
decreased of 56% and of 29% plasmatic levels of triglycerides and LDL-c,
respectively [54]. The same agonist increased HDL-c, apolipoprotein A-1, and
apolipoprotein A-2 in vervet monkeys, a primate atherosclerosis model [81]. The
results of the first human trial, conducted with a small cohort of healthy
volunteers, have shown no toxicity during a treatment period of two weeks with
GW501516 at the doses used for this study [82].
GW501516 has been in a phase II clinical safety/efficacy study for
dyslipidemia, completed in October 2008 by GlaxoSmithKline. The results of this
study have not been published yet. The use of GW501516 could be also a promising
therapeutic approach to prevent multiple aspects of the cardiac fibrotic
process [37, 60]. PPARδ activation and/or overexpression, improving increased
glucose use in diabetic heart, shows promises as a therapeutic strategy for
cardiac dysfunction caused by diabetes and ischemia [22]. Furthermore, the use
of GW0742 may be a new pharmacological approach to protect patients affected by
metabolic syndrome from their elevated risk of ischemic heart disease. GW0742
decreases lipotoxicity, inflammation, and upregulates cell survival [36].
GW0742 and GW501516 could be also used to treat inflammatory diseases such as
atherosclerosis and diabetes [64].MBX-8025 is one
of the most advanced PPARδ agonists currently in a phase II clinical trial for
dyslipidemia and in particular
for its effects on lipid and metabolic parameters, including triglycerides, LDL
and HDL-c, insulin sensitivity, and inflammation. This drug was administrated
alone or in association with Lipitor (atorvastatin, Pfizer Inc., NY, USA), to
patients affected by metabolic syndrome. MBX-8025 depleted substantially the small, dense,
LDL-cholesterol particles, alone or in combination with Lipitor. Other second-generation
PPARδ agonists, CER-002 and KD3010, are in phase I clinical trial
for atherosclerosis and metabolic disorder treatments, respectively [29].Recombinant
adenovirus, bearing a gene that selectively increases PGI2 synthesis
and subsequent PPARδ activation, has been shown to protect neurons from
ischemia/reperfusion in vivo in a model of ischemic cerebral infarction [83].
This could be attributed to the antiapoptotic action of PGI2. Gene
transfer may be used as a new potential treatment for protecting blood vessels
during ischemic diseases through reduction of the vascular cell death.On
the light of these recent findings, we can affirm that PPARδ regulation by
appropriate selective agonists, as well as PPARα and PPARγ activation, could be
used as a novel therapeutic intervention in metabolic and cardiovascular
inflammatory diseases through its effect in atherogenesis control and
angiogenesis regulation. Nevertheless, the long-term use of PPARδ ligands in
patients susceptible to angiogenic diseases, such as diabetics who are prone to
retinopathy or individuals predisposed to cancer, may require particular care
and a better understanding of its possible collateral effects.



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