# PPAR-γ in the Cardiovascular System

Authors: Sheng Zhong Duan; Christine Y. Ivashchenko; Michael G. Usher; Richard M. Mortensen
Journal: PPAR Research
 (2008)

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## Abstract

Peroxisome proliferator-activated receptor-γ  (PPAR-γ), an essential transcriptional mediator of adipogenesis, lipid metabolism, insulin sensitivity, and glucose homeostasis, is increasingly recognized as a key player in inflammatory cells and in cardiovascular diseases (CVD) such as hypertension, cardiac hypertrophy, congestive heart failure, and atherosclerosis. PPAR-γ agonists, the thiazolidinediones (TZDs), increase insulin sensitivity, lower blood glucose, decrease circulating free fatty acids and triglycerides, lower blood pressure, reduce inflammatory markers, and reduce atherosclerosis in insulin-resistant patients and animal models. Human genetic studies on PPAR-γ have revealed that functional changes in this nuclear receptor are associated with CVD. Recent controversial clinical studies raise the question of deleterious action of PPAR-γ agonists on the cardiovascular system. These complex interactions of metabolic responsive factors and cardiovascular disease promise to be important areas of focus for the future.


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## Body

## 1. Introduction

Cardiovascular disease (CVD) is the major cause of morbidity and
mortality  in developed countries [1]. Searching for the underlying
risk factors  has revealed that a cluster of contributors is often present
simultaneously. This risk factor clustering, most notably the core trio of
insulin resistance, dyslipidemia, and hypertension, has been called by a number
of different names including metabolic syndrome (MetS), insulin resistance
syndrome, the deadly quartet, and Syndrome X [1–7]. Although somewhat
controversial, the usefulness of clustering this syndrome remains clear. The
mechanistic connections among the trio are not completely understood.A major focus is to understand the biological and molecular mechanisms
underlying this syndrome and to develop better treatment. One class of
molecules that are proposed to be important in the etiology of MetS is the
nutrient-sensing nuclear transcription factors, peroxisome
proliferator-activated receptors (PPARs), and the related liver X receptors
(LXRs) [7]. Among these nuclear
receptors, PPAR-γ is of intense interest, not only because its ligands, thiazolidinediones (TZDs), are
clinically used for T2DM, but also because it may be a nexus that connects
metabolic disorders to CVD
[1, 4–9]. In addition to its important
roles in insulin sensitivity and glucose homeostasis, PPAR-γ is also associated with CVD such as coronary
heart disease, atherosclerosis, and stroke [7, 10]. MetS is also linked to
cardiac hypertrophy because populations with MetS have higher prevalence of
cardiac hypertrophy [11–14]. However, action of PPAR-γ agonists is not only of metabolism in insulin
responsive tissues, but also more directly in the inflammatory, cardiac, and
vascular cells. The components of MetS are common risk factors to CVD [1]. In this review, we will
focus on PPAR-γ in the
cardiovascular (CV) system, including its expression, gain, and loss of
function, and the mechanisms by which it functions in cardiovascular cells.


## 2. PPAR-γ Gene and Its Expression of CV-Relevant Tissues

PPAR-γ is the most
extensively studied PPAR, even though the cloning of this receptor came four
years later than that of PPAR-α [15]. The PPAR-γ gene extends over more than 100 kb of genomic
DNA. It includes six common coding exons: one exon for the N-terminal A/B
domain, two exons for the DNA binding domain, with each one encoding one of the two
zinc fingers, one exon for the hinge region, and two exons for the ligand binding domain in the
C-terminal region [16, 17]. There are two major splice
isoforms in the mouse, PPAR-γ1 and PPAR-γ2, whereas at least two other isoforms, PPAR-γ3 and PPAR-γ4, have also been identified in other species
including humans [16]. PPAR-γ1 is encoded by eight exons, comprising two γ1-specific exons, A1 and A2, that constitute
the 5′-untranslated region, and the six coding exons that are common to both γ1 and γ2 mRNAs. The PPAR-γ1 protein consists of 477 amino acids [16]. The PPAR-γ2 mRNA is composed of seven exons, the
additional one, exon B, comprising the γ2 5′-untranslated region and an additional
N-terminal amino acid sequence specific for γ2. As a result, PPAR-γ2 is a larger protein, consisting of 505 amino
acids [16].The function PPAR-γ was
initially recognized in adipose tissue [18], although its expression was
first identified in other tissues [15]. It is well expressed in
cardiovascular-system-relevant tissues such as heart, endothelium, vascular
smooth muscle, kidney, and macrophages [10, 19–23].
PPAR-γ2 is mainly expressed in adipocytes while PPAR-γ1 is more widely expressed [23].


## 3. PPAR-γ Ligands

Natural
ligands
Several polyunsaturated fatty acids and their metabolites have
been identified as PPAR-γ ligands
although no ligand has clearly been identified as a critical physiologic
ligand. Endogenous ligands including 15-deoxy-Δ12,14 prostaglandin J2 (15-d-PGJ2) [24]. 15-d-PGJ2 had been one of
the most promising candidates for the endogenous PPAR-γ ligand. It binds to PPAR-γ with a dissociation constant (Kd) in the low-micromolar
range and can activate PPAR-γ target genes
at concentrations at or near the Kd
[25]. However, it has never been
definitively proven to exist in vivo,
nor are its effects that are specific to PPAR-γ [25]. Other natural ligands of
PPAR-γ include 9-
and 13-hydroxyoctadecadienoic acid (HODE), which are components of oxidized low-density
lipoprotein [26], and 12- and 15-hydroxyeicosatetraenoic
acid (HETE) [27].  Some researchers have argued that fatty acids
are the important natural ligands although they are fairly low affinity
ligands.  A recent class of high-affinity
ligands, the nitrolipids, has been identified, but their physiologic function
and the role of PPAR-γ in their
effects have not yet been fully delineated [28].Synthetic ligands
TZDs, or
“glitazones,” are a class of pharmaceutical compounds used clinically as
insulin sensitizers in patients with T2DM [17]. The first clinically used
agent in this class, troglitazone (Rezulin), was removed from the market
because of rare but life-threatening hepatic toxicity. Fortunately, its
successors, rosiglitazone (Avandia), and pioglitazone (Actos), have not been
linked to this side effect [23]. More than 15 million
prescriptions for these TZDs are dispensed annually in the United States
alone. However,
adverse effects such as edema and weight gain have been problematic [23]. Another side effect of TZDs
in animals is cardiac hypertrophy, which has limited the approved doses of
these drugs for clinical use [29–33]. More recently, increased risks of myocardial infarction and
possibly death from cardiovascular causes have been reported to be associated
with rosiglitazone (Avandia) treatment [34], although the result is
controversial [35].TZDs' “on-target” and “off-target”
effects
Compelling evidence has shown that PPAR-γ is the main target of TZDs. PPAR-γ mediates the insulin sensitizing effects of
TZDs in fat, skeletal muscle, and liver [36–39]. TZDs' effects on fluid
retention and weight gain are also dependent on PPAR-γ [40, 41]. However, several studies
demonstrate that some of TZDs' effects are independent of PPAR-γ or “off-target.” In macrophages, it has been
recognized that although TZDs modulate lipid metabolism through PPAR-γ, some of TZDs' anti-inflammatory effects are
independent of it [42] although only at higher
doses. Some of the antiproliferative effects of TZDs in embryonic stem cells [43] or cancer cell lines [44, 45] are independent of PPAR-γ. Further, PPAR-γ in skeletal muscle and liver may not be
mediating TZDs' insulin sensitizing effects under different conditions or in
different models [38, 39, 46]. Loss-of-function studies
have provided additional insight on the possible “off-target” effects of TZDs.
Understanding which TZD effects are PPAR-γ independent is an important issue for
designing more specific PPAR-γ agonists
with fewer side effects. TZDs induce cardiac hypertrophy in animals [29–33] independent of cardiac PPAR-γ [47]. TZDs also increase the incidence of congestive heart
failure [48] presumably due to fluid retention caused by PPAR-γ activation in the kidney [40, 41]. Myocardial infarction
incidence is increased in meta-analysis of
clinical trials [34], but it is not known whether this side effect is mediated by PPAR-γ or whether this finding will be confirmed in a
prospective study [35]. Further, defining the role
of PPAR-γ in these
effects would provide guidance for the design of the next generation of TZDs.


## 4. Gain and Loss of PPAR-γ Function in the CV System

Although originally found to be critical in adipogenesis and regulating
insulin signaling, PPAR-γ is also
important in CV system [16, 17, 49, 50].
Human genetic studies have
revealed that PPAR-γ mutation in
humans can result in either gain-of-function or loss-of-function [51]. In animals, gain-of-function
studies of PPAR-γ have mostly
utilized agonists, particularly synthetic ones (TZDs); Loss-of-function studies
have used knockdown or knockout and transgenic mouse models of mutant PPAR-γ, which are powerful tools to study
physiological mechanisms. The outcome of these approaches in studying PPAR-γ in CV system has been fruitful and sometimes
surprising.Human mutations
Pro12Ala
mutation is a loss-of-function mutation and has been reported to be associated
with not only increased protection against insulin resistance and type-2
diabetes [52–56], but also a decreased incidence of
myocardial infraction [57] and lower diastolic blood pressure [58]. These cardiovascular effects are likely
independent of metabolic impact of this mutation [57, 58].
Pro467Leu, Val290Met, Phe388Leu, and Arg425Cys
are all loss-of-function mutations (dominant negative) and have been associated
with partial lipodystrophy, insulin resistance, diabetes, and hypertension [59–62], although it is not known whether the
elevated blood pressure is due to impaired insulin sensitivity.
C161T mutation is a silent polymorphism and has been reported to be
associated with reduction in coronary artery disease, likely independent of
obesity and of lipid abnormalities, possibly through direct effects on local
vascular wall, implicating the protective role of PPAR-γ in atherogenesis [63].
However, ligand binding domain mutants of PPAR-γ with dominant negative actions have been shown
to be promiscuous, stimulate associations with nuclear receptor corepressor (N-CoR) and silencing mediator of retinoid and thyroid receptors (SMRT), and inhibit
activities of all three wild-type PPARs [64]. These less specific properties of the mutant needs to be explored in the human mutations to determine which effects on metabolic syndrome are mediated through PPAR-γ or the PPARs, PPAR-α or PPAR-δ.Germline gene inactivation
Homozygous
germline PPAR-γ knockout
mice die at E10 due to defects in trophoblast [65, 66]. Heterozygous mutations are
viable, have less adipose tissue, and are more insulin sensitive than wild-type
counterparts [67, 68]. This illustrates the complex
response to gene dosage of PPAR-γ.PPAR-γ and hypertension
PPAR-γ agonists can lower blood pressure and this
effect may be at least partially independent of their insulin-sensitizing
effects [17, 49, 50]. Dominant negative mutation of PPAR-γ (Pro467Leu) in mice results in hypertension
and fat redistribution but not insulin resistance or diabetes seen in the same
mutation in humans [69].  Another line of dominant negative PPAR-γ mutant mice (Leu466Ala)
have hypertension (female only) and insulin resistance [70]. As discussed above, dominant
negative PPAR-γ mutants can
be more promiscuous, inhibiting activity of other PPARs, so we cannot at this
point conclude that these mutants strictly act by altering only PPAR-γ activity [64]. Therefore, comparison to
loss of function mutants and knockouts is critical.
Embryonic lethality of the germline PPAR-γ knockout has been rescued by breeding
Mox2-Cre, in which Cre recombinase is expressed in epiblast-derived tissue but
not other tissues,  to floxed PPAR-γ mice [71]. The generalized PPAR-γ knockout mice have lipodystrophy and insulin
resistance as expected. Surprisingly, they have hypotension rather than
hypertension. This is paradoxical because PPAR-γ agonists lower blood pressure [72–74]. Knockout and agonist having the same
phenotype may be resolved by testing the hypothesis that PPAR-γ suppresses certain key gene expression to
control blood pressure and that both agonist and knockout can relieve the
suppression. Further,
the phenotypes in the generalized PPAR-γ knockout mice suggest that hypertension is separable
from lipodystrophy or insulin resistance, even though they are highly
associated in humans [59, 61] and in A-ZIP mice [71]. Mechanistically, the
vasculature from these generalized PPAR-γ knockout mice has defects in both relaxation
and contraction, contributing to the hypotension.
It has not been completely determined
whether the hypotension phenotype seen in the generalized PPAR-γ knockout mice is attributable to PPAR-γ deficiency in vascular endothelium or smooth
muscle or both. Endothelium-specific PPAR-γ knockout mice are reported to be not having
any phenotype at baseline, although this study only used tail cuff to measure
the blood pressure [75]. When fed with high fat diet,
they have higher blood pressure and heart rate than their wild type control
mice. Rosiglitazone does not affect the diet-induced hypertension in these
knockout mice, although the decrease of blood pressure typically seen in
treated wild-type control mice was not reported [75]. Smooth muscle-specific PPAR-γ knockout mouse model may clarify the role of
smooth muscle PPAR-γ in blood
pressure regulation.
The kidney is an important organ
in controlling blood pressure and PPAR-γ is expressed in this organ, although PPAR-γ deficiency in collecting duct does not alter blood pressure in mice
[40, 41]. The knockout does block weight gain,
fluid retention, and blood volume expansion caused by TZDs [40, 41]. These results indicate that
PPAR-γ deficiency
in collecting duct is unlikely to contribute to the hypotension phenotype seen
in the generalized PPAR-γ knockout
mice [71].PPAR-γ and cardiac hypertrophy
PPAR-γ agonists have been shown to inhibit
hypertrophy of cultured neonatal rat ventricular cardiomyocytes induced by
mechanical stress or angiotensin II, and cardiac hypertrophy induced by aortic
constriction in rats and mice [76–78]. The inhibition on hypertrophy was accompanied by the inhibition on
expression of embryonic genes, including atrial natriuretic peptide (ANP),
brain natriuretic peptide (BNP), skeletal α-Actin, as well as that of endothelin-1 that
can induce cardiac hypertrophy [76–78]. Aortic constriction causes more profound cardiac hypertrophy in
heterozygous PPAR-γ knockout
mice  than wild-type controls, further indicating the involvement of PPAR-γ in cardiac growth [77].
Nuclear Factor-Kappa Beta (NF-κB) pathway is at least partially mediating the
inhibition on hypertrophic growth in vitro [76]. More recently, pioglitazone has been reported to inhibit the gene
expression of inflammatory cytokines such as interleukin (IL)-1β, IL-6 [79], suggesting the possible involvement of PPAR-γ’s anti-inflammatory activity in cardiac
hypertrophy. Paradoxically, TZDs also induce cardiac hypertrophy in mice, rats,
and dogs [30–33].
The cardiomyocyte-specific PPAR-γ knockout mice have age-progressive cardiac
hypertrophy with preserved systolic cardiac function [47]. Rosiglitazone induce cardiac
hypertrophy in both knockout mice and wild-type littermate control mice,
demonstrating that this TZD’s hypertrophic
effect is at least partially independent of PPAR-γ in cardiomyocytes [47]. Whether the cardiac hypertrophy caused by rosiglitazone occurs
through PPAR-γ independent
effects in cardiomyocytes, PPAR-γ in nonmyocyte cells, or blood volume expansion
[33, 48], remains to be further
determined. Studying these knockout mice under pathological stimulations such
as pressure overload may yield more meaningful results to understand the
function of PPAR-γ in the heart.
Rosiglitazone and cardiomyocyte-specific
PPAR-γ knockout
activate distinctly different hypertrophic pathways [47]. Rosiglitazone increases
phosphorylation of both p38 mitogen-activated protein kinase (p38-MAPK) and
extracellular signal-related kinase (ERK) 1/2 in the heart. The activation of p38-MAPK is independent of cardiomyocyte PPAR-γ and that of ERK1/2 is dependent. The
activation of either ERKs or p38-MAPK is sufficient to induce hypertrophy [80, 81] and may therefore contribute
to the cardiac hypertrophy induced by rosiglitazone.
The cardiomyocyte-specific PPAR-γ knockout mouse hearts were found to have
increased expression of cardiac embryonic genes ANP and β-myosin heavy
chain (β-MHC), and
elevated NF-κB activity. Embryonic gene expression in adult hearts
is a one of the characteristics of pathological cardiac hypertrophy [82, 83]. NF-κB is both necessary and sufficient for
hypertrophic growth of cardiomyocytes [84]. Therefore, NF-κB activation is likely to be part of the
mechanisms that PPAR-γ deficiency in cardiomyocytes induces cardiac
hypertrophy. However, the interaction between these two transcription factors
needs to be further characterized.
Another cardiomyocyte-specific
PPAR-γ knockout
mouse line also has progressive cardiac
hypertrophy and accompanied elevation of cardiac gene expression (ANP and
skeletal α-actin) [85]. However, these mice also have dilated cardiomyopathy, heart failure,
and mitochondrial oxidative damage. Increased myocardial superoxide content,
instead of NF-κB activation,
seems to be mediating the severe cardiac phenotype [85]. Similarly, when different
floxed PPAR-γ mice were
used to delete this receptor in skeletal muscle specifically, one mouse line [37] had more severe phenotypes
than the other [46]. It is not clear whether these
phenotypic differences are because of the different genetic design for the
deletion or purely genetic background differences.PPAR-γ, inflammation, and atherosclerosis
PPAR-γ is not only expressed in macrophages,
endothelial cells, and smooth muscle cells in normal vasculature
[10, 19–23], but also in atherosclerotic
lesions [86, 87]. PPAR-γ agonists reduce atherosclerosis in human
patients and animal models [88–92] even though there were
concerns that these compounds could be proatherogenic because they may promote
the macrophages uptake of lipids and speed the foam cell formation [26]. These antiatherogenic effects
can be independent of their beneficial effects on metabolism [93, 94]. More direct antiatherogenic
function of PPAR-γ was demonstrated
by the result that transplantation of PPAR-γ deficient bone marrow to low-density
lipoprotein (LDL) receptor null mice led to a significant increase in
atherosclerosis [95]. The beneficial effects are
largely attributable to PPAR-γ’s
anti-inflammation activity and its role in modulating lipid homeostasis in
macrophages.
Vascular
inflammation has been increasingly appreciated as an important factor in the
pathogenesis of atherosclerosis [96–99]. The importance of macrophage PPAR-γ in CVD has begun to be appreciated since foam
cells in atherosclerotic lesions were found to have high level of PPAR-γ expression [86, 87]. PPAR-γ activation
decreases inflammatory cytokines (e.g., tumor necrosis factor-α, IL-6, and IL-1β) produced by macrophages [100, 101]. By inducing the expression of
LXR-α and ATP-binding cassette A1, PPAR-γ activation promotes cholesterol efflux from
macrophages resulting in inhibition of foam cell formation [95]. Consistently,
macrophage-specific PPAR-γ knockout
mice have reduced basal cholesterol efflux, most likely because of decreased
expression of lipoprotein lipase, scavenger receptor CD36, LXR-α, and ATP-binding cassette G1 [21]. More profound effects on
macrophages by PPAR-γ are also
possible since it has been recently shown that PPAR-γ controls alternative activation of macrophages
and can thereby improve insulin resistance [102].  It is likely that this effect on
differentiation of macrophages is also important in effects of CVD.
Endothelial cells play a key role in the
inflammatory process of vasculature responding to injuries
[96–99]. TZDs have been shown to
reduce superoxide generation and inhibit the expression of vascular cell
adhesion molecule-1, intercellular cell adhesion molecule-1, and lectinlike
oxidized LDL receptor, and hence inhibit inflammation in endothelial cells [103–106], suggesting an important role
of endothelial PPAR-γ in the
development of atherosclerosis. The existing endothelium-specific PPAR-γ knockout mice [75] and generalized PPAR-γ knockout mice [71] can be useful tools to study
the function of endothelial PPAR-γ in atherosclerosis.
Different
cell types are reported to have different mechanisms for PPAR-γ to inhibit inflammation. In intestinal Caco-2 cells, PPAR-γ inhibits inflammation by binding to NF-κB and facilitating its nuclear export [107]. In macrophages, PPAR-γ prevents corepressor complex N-CoR
dissociation from the promoters of NF-κB responsive inflammatory gene inducible nitric oxide synthase and
therefore represses its expression [108]. It remains to be determined whether PPAR-γ in endothelial or other vascular cells uses one of these pathways or an
entirely different mechanism.
The growth and movement of vascular smooth muscle cell within neointima
is one of the key steps leading to the formation of atherosclerotic plaque
[96]. PPAR-γ agonists have been shown to block the
proliferation and increase the apoptosis of vascular smooth muscle cells,
suggesting more beneficial effects of PPAR-γ activation in vasculature [109, 110].PPAR-γ and cardiac remodeling
Cardiac remodeling
after ischemic injury is one of the major causes that lead to heart failure [111, 112]. The remodeling process is
characterized by myocyte hypertrophy and cardiac fibrosis
[111, 112]. PPAR-γ agonists
attenuate this remodeling process after ischemia in experimental animals
[113]. Recent  in vitro studies on PPAR-γ in cardiac
fibroblasts, a major source of fibrillar collagens that lead to fibrosis
[111, 112], have revealed more mechanistic
insights.
Pioglitazone reduces cell growth, synthesis
of collagen type I, and expression of matrix metalloproteinase-1 in cardiac
fibroblasts undergone anoxia-reoxygenation or treated with angiotensin II,
likely through inhibition of reactive oxygen species generation and NF-κB
activation [114, 115]. Brain natriuretic peptide has
been implicated in these effects
[116]. In cultured cardiac
fibroblasts, PPAR-γ agonists
induce the expression of vascular endothelial growth factor, a crucial player
in the infarcted/ischemic heart, further indicating the beneficial effects of PPAR-γ agonists in cardiac remodeling [117]. However, all of these
studies are based upon gain-of-function results. Further investigation using
loss-of-function studies would advance our understanding the role of PPAR-γ in cardiac fibroblasts and cardiac remodeling
and provide more therapeutic guidance.PPAR-γ in cardiovascular side effects of TZDs
Despite the obviously beneficial effects that TZDs have in CV system
[118], these compounds have some
cardiovascular side effects that are dangerous to be overlooked. As mentioned
above, TZDs induce cardiac hypertrophy in animals, a limitation to the dosages in their clinic use.
Congestive heart failure remains to be one
of the major contraindications to the clinical use of TZDs
[48].  This is presumed to be secondary to the fluid
retention caused by activation of PPAR-γ in the kidney, likely in the
collecting duct [40, 41].  Collecting duct knockouts of PPAR-γ is able to excrete salt loads more easily
although there is no end effect on blood pressure on normal salt diets
[40, 41].
PPAR-γ knockout blocked the effect of TZD on mRNA
expression of the sodium channel ENaC-γ although the baseline level
in the knockout
was higher [40].
One recent report regarding the association
between rosiglitazone treatment and significantly increased risk in myocardial
infarction as well as an increased risk with borderline significance in death
from cardiovascular causes has brought a lot of attention to the safety of this
drug  [34]. The findings were based on
limited access to the original data, and meta-analysis
used to reach the conclusions is always
considered less convincing than a large prospective trial designed to assess
the outcome of interest. Such a prospective study is indeed ongoing and
the investigators performed an interim analysis and found that rosiglitazone
was not significantly associated with increased risk of myocardial infarction
and death from cardiovascular causes, although the findings were inconclusive
because of the incompleteness of the study  [35]. One side effect of
rosiglitazone this interim analysis did confirm is the increased incidence of
heart failure   [35].
Although the findings need to be confirmed,
the possible adverse effects of rosiglitazone in myocardial infarction and
death from cardiovascular causes are worrisome due to the fact that diabetic
patients are already at higher risk for cardiovascular diseases. The mechanisms
of the possible adverse effects are uncertain, and could involve myocardial as
well as vascular changes. Pioglitazone, another member in the same TZD class, does
not seem to have these side effects  [119]. In comparison to
rosiglitazone, pioglitazone appears to have more beneficial effects on lipid
profile  [120], which may be one of the
contributors to these side effects. However, the exact mechanisms and molecular
basis are yet to be explored. In order to ultimately understand this drug and
help new drug design, it is critical to address questions such as whether PPAR-γ is mediating these effects of rosiglitazone
and whether heart (cardiomyocytes, cardiac fibroblasts, endothelial cells, or
smooth muscle cells) is the direct target.
The cardiovascular phenotypes of these gain- or loss-of function studies
are summarized in Table1.Table 1
Cardiovascular phenotypes in gain and loss of PPAR-γ function.
CHMIBPCADASTZDsAgonismGain of function↑*[30–33, 47]↑**[34]↓[17, 49, 50]↓[87–91]Pro12AlaHuman mutationLoss of function↓[57]↓[58]Pro467LeuHuman mutationLoss of function↑[59, 60]Val290MetHuman mutationLoss of function↑[60]Phe388LeuHuman mutationLoss of function↑[61]Arg425CysHuman mutationLoss of function↑[62]C161THuman mutationLoss of function↓[63]Pro467LeuMouse mutationLoss of function↑[69]Leu466AlaMouse mutationLoss of function↑[70]Generalized KOTransgenic mouseLoss of function↑[71]↓[71]Cardiac KOTransgenic mouseLoss of function↑[47]Endothelial KOTransgenic mouseLoss of function→[75]Collecting duct KOTransgenic mouseLoss of function→[40, 41]TZDs: thiazolidinediones; KO: knockout; CH: cardiac hypertrophy;MI: myocardial infarction; BP: blood pressure; CAD: coronary artery disease; AS: atherosclerosis*: in animals only; **: rosiglitazone onlyNumbers in square brackets are the reference numbers.


## 5. Conclusions

PPAR-γ is now firmly established as an important
player in cardiovascular diseases. Understanding the mechanisms of PPAR-γ action in heart and vascular cells where
action on NF-κB appears to
be important in controlling growth and inflammation may lead to improved
targeting of the PPAR-γ activity in
these cells. The interactions of PPAR-γ with other
nuclear transcription factors which have partially overlapping effects
such as the PPAR-α, PPAR-δ, and LXR will likely reveal a complex control
system of inflammatory and growth responses to nutrient signaling.



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