Significance of peroxisome proliferator-activated receptors in the cardiovascular system in health...

Pharmacology & Therapeutics 122 (2009) 246–263

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Pharmacology & Therapeutics

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Associate editor: B.J. McDermott

Significance of peroxisome proliferator-activated receptors in the cardiovascularsystem in health and disease

Emma Robinson, David J. Grieve ⁎Centre for Vision and Vascular Science, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, 3rd Floor, Medical Biology Centre, 97 Lisburn Road,Belfast, BT9 7BL UK

Abbreviations: ACE, Angiotensin-converting enzymepeptide; COX, Cyclooxygenase; CVD, Cardiovascular diregulated kinase; ET, Endothelin; FATP, Fatty acid transdomain; LDL, Low density lipoprotein; L-NAME, N-nitrprotein-1; MI, Myocardial infarction; MMP, Matrix meNuclear factor-kappa B; NO, Nitric oxide; NOS, Nitric oactivated receptor; PPRE, Peroxisome proliferator responmediator for retinoid and thyroid hormone receptor; STA⁎ Corresponding author. Tel.: +44 2890972097; fax:

E-mail address: [email protected] (D.J. Grieve).

0163-7258/$ – see front matter © 2009 Elsevier Inc. Aldoi:10.1016/j.pharmthera.2009.03.003

a b s t r a c t
a r t i c l e i n f o
Keywords:
Peroxisome proliferator-activated receptor(PPAR)Cardiovascular disease (CVD)HeartAtherosclerosisHypertensionHypertrophy
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors thatbelong to the nuclear receptor superfamily. Three isoforms of PPAR have been identified,α, δ and γ, which playdistinct roles in the regulation of key metabolic processes, such as glucose and lipid redistribution. PPARα isexpressed predominantly in the liver, kidney and heart, and is primarily involved in fatty acid oxidation. PPARγis mainly associated with adipose tissue, where it controls adipocyte differentiation and insulin sensitivity.PPARδ is abundantly and ubiquitously expressed, but as yet its function has not been clearly defined. Activatorsof PPARα (fibrates) and γ (thiazolidinediones) have been used clinically for a number of years in the treatmentof hyperlipidaemia and to improve insulin sensitivity in diabetes. More recently, PPAR activation has beenfound to confer additional benefits on endothelial function, inflammation and thrombosis, suggesting thatPPAR agonists may be good candidates for the treatment of cardiovascular disease. In this regard, it has beendemonstrated that PPAR activators are capable of reducing blood pressure and attenuating the development ofatherosclerosis and cardiac hypertrophy. This review will provide a detailed discussion of the currentunderstanding of basic PPAR physiology, with particular reference to the cardiovascular system. It will alsoexamine the evidence supporting the involvement of the different PPAR isoforms in cardiovascular disease anddiscuss the current and potential future clinical applications of PPAR activators.

© 2009 Elsevier Inc. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2462. PPARs and the cardiovascular system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2503. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254

258258258

; AF, Activation function; ANF, Atrial natriuretic factor; Ang II, Angiotensin; AP-1, Activator protein-1; BNP, Brain natriureticsease; DBD, DNA binding domain; DHA, Docosahexaenoic acid; DOCA, Deoxycorticosterone acetate; ERK, Extracellularport protein; HDL, High density lipoprotein; ICAM, Intercellular adhesion molecule; IL, Interleukin; LBD, Ligand bindingo-L-arginine methyl ester; LV, Left ventricular; MAPK, Mitogen activated protein kinase; MCP-1, Monocytic chemotactictalloproteinases; NADPH, Nicotinamide adenosine dinucleotide phosphate; NcoR, Nuclear receptor co-repressor; NF-κB,xide synthase; PGC-1, Peroxisome proliferator-activated receptor gamma co-activator-1; PPAR, Peroxisome proliferator-se element; ROS, Reactive oxygen species; RXR, Retinoid X receptor; SHR, Spontaneously hypertensive rats; SMRT, SilencingT, Signal transducers and activator of transcription; TNFα, Tumour necrosis factorα; VCAM, Vascular cell adhesionmolecule.+44 2890975775.

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247E. Robinson, D.J. Grieve / Pharmacology & Therapeutics 122 (2009) 246–263

1. Introduction

Despite major therapeutic advances, cardiovascular disease (CVD)remains one of the leading causes of morbidity and mortality in thewestern world. Traditional risk factors for CVD include hypertension,hyperglycaemia and dyslipidaemia (Kannel, 1997). However therapidly increasing incidence of metabolic disorders such as diabetes,obesity and metabolic syndrome combined with more aggressivetreatment of hypertension is shifting the underlying aetiology towardshyperglycaemia and dyslipidaemia. CVD is frequently characterised bydysregulation of fatty acids, particularly in patients with metabolicdisease (Abate, 2000; Grundy, 2004). In healthy individuals the ratesof uptake and utilisation of fatty acids are tightly controlled in order tomatch tissue energy demands and maintain lipid balance. However,when this balance is upset the subsequent increase in circulating fattyacids becomes a primary risk factor for the development of hyperten-sion and atherosclerosis (Egan et al., 2001). Several classes of drugs,including bile acid sequestrants, fibrates and statins, have been usedhistorically to reduce cholesterol levels and maintain physiologicalplasma concentrations (Knopp, 1999). Of these, statins have nowbecome the primary therapeutic choice for CVD prevention, subse-quent to several large-scale primary and secondary clinical trialswhich demonstrated that chronic treatment caused a significantreduction in the incidence of coronary heart disease (ScandinavianStudy Simvastatin Survival Group Study 1994; Shepherd et al., 1995).Nevertheless, there remains a substantial incidence of CVD inoptimally-treated patients, especially thosewith additional underlyingpathologies, such as diabetes. In the ongoing search for amore effectivealternative to statins, recent attention has begun to focus on fibratesand thiazoldidenodiones, due to their therapeutic value in the specifictreatment of hyperlipidaemia and diabetes, respectively. These drugsexert their effects via activation of peroxisome proliferator-activatedreceptors (PPARs), which belong to the nuclear hormone receptorsuperfamily. This review will discuss the current understandingof PPAR physiology and pharmacology and how activation of thePPAR pathway may modify the development of several diseases of thecardiovascular system.

1.1. PPAR discovery and classification

Peroxisomes are subcellular organelles whose classical role is toremove hydrogen through the use of molecular oxygen via a seriesof oxidase and catalase enzymes. They also play a crucial role inseveral cellular metabolic processes, including the catabolism ofcholesterol to bile and the β-oxidation of fatty acids. Under normalphysiological conditions, peroxisomemetabolism occurs secondary tothat in the mitochondrial system (Vamecq & Drey, 1989), andprimarily involves oxidation of very long-chain fatty acids that cannotbe otherwise metabolised. In rat liver cells activation of peroxisomesby various pharmacological stimuli has been shown to induceperoxisomes to increase in size and number (Reddy & Krishnakantha,1975; Lock et al., 1989), and is associated with an increased expressionof genes involved in fatty acid oxidation. In humans, pharmacologicalagents may activate peroxisomal gene transcription in a similarmanner but in contrast to the rat there is no corresponding increase in

Fig. 1. Schematic Structure of PPAR. PPARs have six structural regions and four functional domactivation function (AF-1). The C domain promotes PPAR binding to a DNA sequence. The C-treceptor. The D domain or “hinge” domain links the DNA binding domain to the ligand bindinto assist the transcription process via the ligand-dependent transactivation function (AF-2)

peroxisome size or number (Kliewer et al., 2001). The group ofstructurally disparate compounds, which were initially found tostimulate peroxisome proliferation in rats, were assigned as peroxi-some proliferators although the mechanism of action of thesecompounds was unknown at that time.

In 1990, the cloning of a mouse gene linked to peroxisomeproliferation was first described (Isseman & Green 1990). It was subse-quently discovered that peroxisome proliferators acted via stimulationof an orphan nuclear hormone receptor, which was named theperoxisome proliferator-activated receptor or PPAR; the original receptoris now known as PPARα. Together, PPARs form group C in subfamily 1of the superfamily of nuclear hormone receptors, i.e., NR1C. The largenuclear receptor superfamily comprises ligand-activated transcriptionalfactors that regulate the expression of a large number of genes involvedin carbohydrate and lipid metabolism (Giguere, 1999). Also includedin this group are the steroid, thyroid, vitamin D and retinoic acidreceptors, as well as several other orphan receptors for which aligand/activator has yet to be identified (Manglesdorf et al., 1995;Blumberg & Evans 1998). Leading on from the discovery of theprototypic mouse PPAR, (PPARα, NR1C1), the cDNA of two othermajor isotypes of this nuclear receptor subfamily, PPARδ (NR1C2)and PPARγ (NR1C3), were identified, although neither of these PPARsubtypes were found to be associated with peroxisome prolifera-tion. All three PPARs are encoded by separate genes and have beenfound to be expressed in amphibians (Dreyer et al., 1992), rodents(Gottlichter et al., 1992; Kliewer et al., 1994) and humans (Schmidtet al., 1992; Sher et al., 1993; Greene et al., 1995). PPARα and PPARγappear to be highly conserved across species, whereas PPARδ isconsiderably divergent (Kliewer et al., 1994).

1.2. PPAR structure and mechanism of action

PPARs are compact ligand-activated transcription factors thatcontrol gene expression and have a structural organisation compar-able to the other members of the nuclear hormone receptor family.PPARs have five or six structural regions within four functionaldomains, known as A/B, C, D and E/F, as depicted in Fig. 1. The amino-terminal A/B domain, which is poorly conserved between the threePPAR isotypes, contains a ligand-independent activation function-1(AF-1) (Werman et al., 1997). Phosphorylation in this region modulatesreceptor activity in an isotype-dependent manner; for example,insulin can stimulate PPARα-mediated transcription via mitogen-activated protein kinase (MAPK)-induced phosphorylation at Ser12and Ser21 (Shalev et al., 1996; Juge-Aubry et al., 1999), whereas MAPK-mediated phosphorylation of Ser112 has an inhibitory action on PPARγ(Adams et al., 1997; Camp & Tafuri, 1997). The 70 amino acid longDNA binding domain (DBD) or C domain is comprised of two highlyconserved zinc finger-like structures and promotes binding of thereceptor to a DNA sequence in the promoter region of target genes,known as the peroxisome proliferator response element (PPRE)(Kliewer et al., 1992). The C-terminal, E/F domain or ligand bindingdomain (LBD) is responsible for ligand specificity and activation of PPARbinding to the PPRE of target genes. The D domain or “hinge” domainlinks the DBD to the LBD and acts as a docking site for co-factors. The Nterminal or E/F domain recruits co-factors to assist the transcription

ains A/B, C, D and E/F. The amino-terminal A/B domain contains a ligand-independenterminal, E/F domain or ligand binding domain is responsible for ligand specificity of theg domain and acts as a docking site for co-factors. The E/F domain also recruits co-factors.

Fig. 2. Basic mechanism of action of PPARs. PPARs bind to a specific sequence in thepromoter of target genes (peroxisome proliferator response element; PPRE) andactivate transcription. The PPAR/retinoid X receptor (RXR) heterodimer binds to thePPRE with PPAR occupying the 5′half site whilst RXR occupies the 3′ half site. The PPREconsensus sequence, 5′-AGGTCA n AGGTCA-3′, fits a DR1 pattern of two direct repeatsspaced by one nucleotide, and is specific for the PPAR/RXR heterodimer, setting it apartfrom other nuclear receptors.

248 E. Robinson, D.J. Grieve / Pharmacology & Therapeutics 122 (2009) 246–263

process via the ligand-dependent transactivation function (AF-2)(Berger & Moller, 2002).

Upon activation by endogenous or synthetic ligands, PPARs, likeother nuclear hormone receptors, form obligate heterodimers withthe 9-cis retinoic acid receptors (retinoid X receptor, RXR), a processfacilitated by the LBD. The resulting complex undergoes a conforma-tional change which allows binding of the heterodimer to the PPRE(consensus sequence: 5′-AGGTCA n AGGTCA-3′), which is located inthe promoter region of the target gene (Torra et al., 2001). The PPAR/RXR heterodimer binds to the PPRE with PPAR occupying the 5′ halfsite, whilst RXR occupies the 3′ half site. The PPRE consensus sequence(5′-AGGTCA n AGGTCA-3′) fits a pattern of two direct repeats spacedby one nucleotide (DR1), and is specific for the PPAR/RXR hetero-dimer, setting it apart from other nuclear receptors, such as thethyroid or vitamin D receptors (Ijpenberg et al., 1997; Kliewer et al.,2001). Binding of the heterodimer complex to the PPRE is diagram-matically represented in Fig. 2. Ligands of either of the heterodimericreceptors are able to independently induce transcription of targetgenes, but when both PPAR and RXR are activated simultaneously, itresults in significant synergistic enhancement of gene transcription(Kleiwer et al., 1992; Mangelsdorf & Evans, 1995).

1.3. Co-activators/repressors of PPARs

Many proteins act as co-activators or co-repressors that regulatethe ability of nuclear hormone receptors, such as PPARs, to eitherstimulate or repress gene transcription. PPARs do not appear to beactive under basal conditions. In the unbound state, PPAR/RXRheterodimers are associated with co-repressors, such as silencingmediator for retinoid and thyroid hormone receptor (SMRT) andnuclear receptor co-repressor (NcoR), which prevent gene transcrip-tion through their histone deacetylase activity (Chen & Evans, 1995;Horlein et al.,1995; Xu et al.,1999). However, once a ligand binds to thereceptor a conformational change occurs that not only facilitates co-repressor dissociation, but also the recruitment of several positive co-activators, including PBP, PPARγ binding protein and steroid receptorco-activator 1 (SRC-1) (Zhu et al., 1997; Nolte et al., 1998). Morerecently identified co-activators include the PPARγ co-activator-1(PGC-1) proteins, PGC-1α (Puigserver et al., 1998) and PGC-1β (Lin etal., 2002), both of which are found in tissues which exhibit a high rateof mitochondrial metabolism. Once a ligand becomes bound to thereceptor, the histone acetylase activity intrinsic to these co-activators

initiates a sequence of events which ultimately lead to genetranscription (Soutoglou et al., 2001). Although co-activators and co-repressors appear to be the major factors responsible for regulation ofPPAR activity, these receptors can also bemodulated byMAPK-inducedphosphorylation, adding a further dimension to an already intricatesystem of control. For example, phosphorylation by extracellularregulated kinases (ERK) has been found to repress PPARα activity(Barger & Kelly, 2000), whereas that induced by p38 MAPK activationenhances PPARα-mediated gene expression (Barger et al., 2001).

1.4. PPAR ligands

PPARs have a remarkable ability to be activated by a wide range ofstructurally diverse endogenous and synthetic ligands. However,heterogeneity of the LBD between the three PPAR isotypes is suchthat there is a degree of ligand specificity. Among the syntheticligands, fibrates (e.g. Wy 14,643, clofibrate, gemfibrozil, fenofibrate,bezafibrate) are a class of hypolipidemic drugs which are commonlyused to reduce plasma triglycerides, an established risk factor for thedevelopment of CVD. Although the majority of fibrates preferentiallyactivate PPARα, few are specific. Wy 14,643 and clofibrate were thefirst reported activators of PPARs; they are selective for PPARα atconcentrations up to 10 μM, but at higher concentrations also activatePPARγ (Lehmann et al., 1997). Other PPAR agonists appear to have ahigher affinity for PPARα, such as GW2331, which has a Kd of 140 nM(Kliewer et al., 1997). Glitazones are thiazolidinedione-based anti-diabetic compounds which are preferential agonists of PPARγ. Ciglita-zone was originally derived from clofibrate by optimisation of its weakglucose-lowering properties. In addition to these anti-hyperglycaemicactions, ciglitazone was also found to reduce glucose levels whilstretaining some of the lipid-lowering properties of fibrates. Since theirinitial discovery, more potent derivatives have been developed, such asrosiglitazone, pioglitazone and troglitazone (Kliewer et al., 2001). Ingeneral, PPARγ agonists show greater selectivity than those of PPARα;for example, rosiglitazone, the first high affinity PPARγ ligand to beidentified, has a Kd of 43 nM as compared to the micromolar affinitiescommonly associated with fibrates.

In addition to agonists of PPARα and PPARγ which have wideclinical applications, synthetic ligands for PPARδ have also beendeveloped (Berger et al., 1999). L165041, a phenoxyacetic acidderivative and GW0742X (Michalik et al., 2006) act as specificPPARδ agonists, which may have beneficial effects on lipid andglucose metabolism, in addition to playing a role in fertility andcancer. Despite concerted efforts to develop high affinity, isotype-specific PPAR agonists, it is becoming increasingly apparent that manysynthetic PPAR ligands also exert PPAR-independent effects. Whilstmuch of the PPAR research to date employing such synthetic agonistshas provided tremendous insight into PPAR biology, the results ofthese studies must be interpreted with care. It is clear that theexistence of a specific endogenous ligand would enable a morefocussed interrogation and detailed understanding of PPAR function,and considerable effort has been invested in this direction. The maincandidate for an endogenous PPAR activator appears to be fatty acids,which are known to possess similar characteristics to fibrates;however, whether or not they are true natural PPAR ligands is stillopen to debate. An early investigation revealed that PPARα isactivated by long-chain fatty acids (Gottlicher et al., 1992), andsubsequently the ability of individual fatty acids of variable chainlength and degree of saturation to act as ligands for the three PPARisotypes has become the focus of many in vitro studies. PPAR subtypeshave varying affinities for different fatty acids. For example, PPARαand PPARδ have comparable affinities for long-chain saturated, mono-and poly-unsaturated fatty acids, whereas PPARγ has a very lowaffinity for saturated fatty acids (Forman et al., 1997; Johnson et al.,1997; Kliewer et al., 1997; Xu et al., 1999). However, the in vitroaffinities of the these fatty acids for their respective PPARs are in the


micromolar to submillimolar range; if they were to be true selectiveendogenous ligands these affinities should be at much lowerconcentrations, within the nanomolar range.

Another factor in consideration of fatty acids as potential endogen-ous PPAR ligands is the mechanism by which these labile moleculescould become sufficiently concentrated within the nucleus so as toactivate PPAR. In this regard, it has recently been shown that both localgenerationwithin thenucleus via the action of phospholipases and fattyacid transport may be involved in fatty acid-mediated PPAR activation(Han et al., 2002; Tan et al., 2002; Gilde & Van Bilsen, 2003). Certainderivatives of fatty acids are also capable of binding to PPARs, withproducts of lipooxygenase and cyclooxygenase metabolism appearingto bemore specific and potent than their fatty acid precursors. Indeed, ametabolite of the prostaglandin J2 group, 15d-PGJ2 and prostacyclinhave previously been suggested to be natural ligands for PPARγ andPPARδ, respectively, due to their high affinities for each receptor(Forman et al., 1995; Kliewer et al., 1995; Lim et al., 1999). Despite this,recent evidence has demonstrated that 15d-PGJ2 exerts PPARγ-independent effects (Kaplan et al., 2007) which imply that it is not anendogenous PPARγ ligand. Details of the endogenous and syntheticagonists of PPARs and their typical EC50 values are given in Fig. 3.

1.5. Selective PPAR modulators (SPPARM)

Upon binding to PPARs, different ligands can induce differentstimulatory or inhibitory responses depending on the nature of thespecific target gene and its cellular location, a principle which hasbeen termed the selective PPAR modulator (SPPARM) theory. Itsuggests that once ligands become bound to the receptor, they caneach induce unique and distinct conformational changes, leading todifferential co-activator/co-repressor interactions, enabling subtledifferences in transcriptional activation of target genes. Therefore,distinct ligands for one common receptor are capable of inducing

Fig. 3. Table of typical EC50 values for endogenous and synthetic PPAR ligands at murine PPAPPARα, and the glitazones, a thiazolidinedione-based group of anti-diabetic compounds whfatty acids or their derivatives.

different physiological responses depending on, for example, cell type.The SPPARM theory is currently being employed to aid the develop-ment of new generation PPAR agonists, with the hope that specificcompounds may be identified that are capable of activating thetranscription of desirable target genes whilst minimising/repressingthe transcription of those which are detrimental (Chinetti-Gbaguidiet al., 2005a; Fruchart, 2007).

1.6. Tissue distribution of PPARs

In order to begin to understand the complex physiological role ofthe different PPARs, it is essential to examine their tissue expression.In both rodents and humans, PPARα is predominantly expressed incells with high rates of fatty acid catabolism and peroxisome-dependent oxidation, such as those found in liver, heart, kidney,skeletal muscle, pancreas and intestinal mucosa (Braissant et al., 1996;Schoonjans et al., 1996a). PPARγ is mainly associated with adiposetissue, with a low level of more ubiquitous expression in liver, heart,skeletal muscle and bone marrow (Escher & Wahli, 2000). Interest-ingly, splice variants of the human PPARγ (PPARγ1 and PPARγ2) andmore recently, PPARα have been identified (Fajas et al., 1997; Gervoiset al., 1999). PPARγ2 has been found to be exclusively and abundantlyexpressed in fat tissue, whereas PPARγ1 has a more ubiquitousexpression profile (Schoonjans et al., 1996b). PPARδ is abundantly andubiquitously expressed at much higher levels than PPARγ and PPARα(Kliewer et al., 1994). It is important to note that tissue expression ofall three PPAR isotypes is likely to vary under differing physiologicaland/or pathological conditions.

1.7. Physiological function of PPARs

Activation of PPARs is a multifaceted process that relies on efficientreceptor dimerisation, co-factor recruitment, phosphorylation and

R receptors. Synthetic PPAR agonists include the fibrates, which preferentially activateich are preferential agonists of PPARγ. Endogenous PPAR activators are predominantly


ligand binding. The diverse physiological responses elicited by PPARactivation are made possible by the complexities of the receptoractivation pathway and the disparate tissue expression of eachreceptor subtype.

1.7.1. PPARαIdentification of PPAR target genes first illustrated that PPARα is a

major regulator of fatty acid homeostasis. PPARα controls theexpression of a wide range of proteins involved in both the transportand β-oxidation of free fatty acids. Specifically, PPARα plays a criticalrole in the regulation of fatty acid transport protein (FATP), whichfacilitates the uptake of long-chain fatty acids across the plasmamembrane, and several key enzymes involved in their subsequentcatabolism within the cell. PPARα has been shown to induceactivation of acyl-CoA oxidase, thiolase, acyl-CoA dehydrogenaseand cytochrome P450 ω-hydroxylase, which are all essential to theβ-oxidation of fatty acids within peroxisomes, mitochondria andmicrosomes (Schoonjans et al., 1996b). It has been suggested thatPPARα may also act as a cellular sensor capable of detecting changesin circulating free fatty acids or their associated metabolites andintermediates. PPARα-stimulated expression of lipoprotein lipaseis known to promote the release of fatty acids from lipoproteinparticles and their subsequent uptake (Schoonjans et al., 1996b).PPARα expression has also been found to be significantly increasedin situations of metabolic stress, such as fasting or severe cold, whenincreased energy production requires the release of fatty acids fromadipose tissue (Lemberger et al., 1996). Definitive evidence tosupport the critical requirement of PPARα for effective lipid handlingcomes from a study in PPARα null mice which examined the effectof pharmacologic inhibition (etomoxir) of mitochondrial fatty acidimport on lipid metabolism.Whereas wild-type animals were able totolerate etomoxir treatment, PPARα null mice exhibited preferentiallipid accumulation in tissues with a high rate of lipid oxidation, suchas liver, heart and kidney, which may ultimately lead to lipotoxicityand death (Djouadi et al., 1998). Indeed, PPARα agonists are widelyused in the treatment of disorders characterised by elevated levels ofplasma lipids, i.e. dyslipidaemias. Fibrates exert their positive effectson lipid handling by inducing hepatic uptake and β-oxidation of fattyacids and increasing lipoprotein lysis, whilst also conferring beneficialeffects on the high density lipoprotein (HDL) to low density lipoprotein(LDL) ratio.

PPARα activation has also been shown to have anti-inflammatoryeffects. In gene-modified mice lacking PPARα, a considerablyprolonged inflammatory response was observed, and this wassuggested to be due to degradation of the chemotatic inflammatorymediator, leukotriene B4 (Devchand et al., 1996). Increasing evidencesuggests that PPARα may mediate its anti-inflammatory actionsthrough reduced generation of cytokines. This may occur secondary todownregulation of the activity of nuclear factor-kappa B (NF-κB) andinducible cyclooxygenase-2 (COX-2) (Poynter & Daynes, 1998; Staelset al., 1998).

PPARα-induced peroxisome proliferation has been associated withthe development of hepatic carcinomas in rodents, possibly due toincreased production of H2O2 in the absence of a compensatory rise incatalase activity (Gonzalez et al., 1998). However, this is likely to be oflittle clinical relevance due to the absence of peroxisome proliferationin humans upon PPARα activation. Furthermore, the concentration ofPPARα agonist required to stimulate lipidmetabolism (as desiredwithfibrate treatment) would be too low to stimulate the transcriptionalinduction of genes involved in peroxisome proliferation (Chevalier &Roberts, 1998).

1.7.2. PPARγPPARγ acts as a primary regulator of adipocyte differentiation in

the process of adipogenesis. Once fully matured, adipocytes arecapable of producing various hormones and cytokines, in addition to

the uptake and storage of lipids. Activation of PPARγ upregulates theexpression of genes involved in fatty acid uptake and lipogenesis aswell as glucose transporters (Shimaya et al., 1998). PPARγ activationalso promotes apoptosis inmature adipocytes, resulting in stimulationof adipogenesis and the formation of small insulin-sensitive adipo-cytes (Okuno et al., 1998). This is one potential mechanism by whichthiazolidinediones may improve insulin sensitivity in diabetes. PPARγis known to regulate many genes involved in insulin signalling, such asthose that control the expression of the pro-inflammatory cytokine,tumour necrosis factor α (TNFα). PPARγ activation significantlyreduces the production of TNFα by adipocytes, which plays anestablished role in the development of insulin resistance (Moller,2000). In diabetes, PPARγ improves overall glucose homeostasis byincreasing glucose transport in adipocytes, regulating adipocyte-derived hormone release, decreasing glucose formation and increas-ing glucose disposal in skeletal muscle (Kota et al., 2005). A recentstudy by Odegaard et al. (2007) has suggested that macrophage-specific PPARγ activation also reduces insulin resistance in adiposetissue via differentiation of alternatively activated monocytes with ananti-inflammatory phenotype. Indeed, PPARγ, like PPARα, appears toexert significant anti-inflammatory effects. PPARγ expression ismarkedly increased in activated macrophages, and stimulation ofthese upregulated receptors by the PPARγ activator PGJ2, has beenshown to inhibit the activity of NF-κB, STAT and activator protein-1(AP-1). These transcription factors are all known to increase theexpression of genes encoding pro-inflammatory cytokines (Ricoteet al., 1998a), production of which has also been demonstrated to bereduced by PPARγ activation in human monocytes (Jiang et al., 1998).Non-steroidal anti-inflammatory drugs, such as ibuprofen anddiclofenac, can activate PPARγ at concentrations higher than thoserequired for their characteristic COX activity. This activation has alsobeen associated with the inhibition of cytokine production frommonocytes, suggesting that endogenous intermediates which nor-mally activate the COX pathway may potentially exert an additionalopposing anti-inflammatory role through activation of PPARγ.

The fact that PPARγ activation stimulates cellular differentiationand apoptosis suggests that this approach may be beneficial in thetreatment of cancers. Indeed, PPARγ agonists have been demonstratedto have potent anti-tumour effects in breast (Mueller et al., 1998),prostate (Kubota et al., 1998) colon (Jackson et al., 2003) and gastric(Sato et al., 2000) malignancies in both isolated cell and whole animalstudies. However, it is not yet knownwhether these benefits extend tothe clinical arena.

1.7.3. PPARδDue to the ubiquitous nature of the expression of PPARδ, it has

been implicated in a variety of physiological and pathophysiologicalprocesses. Like PPARα and γ, PPARδ plays a role in the regulation ofcirculating lipid and glucose levels (Berger et al., 1999). PPARδ has alsobeen suggested to modulate insulin resistance through activation ofalternatively activated macrophages which inhibit inflammation inboth adipose tissue and liver (Kang et al., 2008; Odegaard et al., 2008).Furthermore, it appears likely that PPARδ activation may be involvedin fertility and pregnancy, as PPARδ is highly expressed in implanta-tion sites within the uterus (Lim et al., 1999; Ding et al., 2003). PPARδwas initially implicated in tumour development (Gupta et al., 2000),but more recent work suggests that activation of PPARδ may in factattenuate carcinogenesis (Harman et al., 2004). The fact that PPARδ ishighly expressed in the central nervous system has generated muchinterest in a potential role in neural pathologies, and this is the subjectof ongoing research.

2. PPARs and the cardiovascular system

PPARs are widely expressed in both the vasculature and themyocardium, as well as in immune cells such as monocytes and


macrophages. In addition to their role in transcriptional activation, inthe unbound state, PPAR-RXR heterodimers can also repress targetgene expression. Hence, PPARs can exert positive and negativeregulatory control over a range of genes involved in metabolism andinflammation (Bensinger & Tontonoz, 2008). As a result, their impacton cardiovascular (patho)physiology stretches far beyond theirestablished effects on carbohydrate and lipid metabolism. This sectionwill discuss the involvement of different PPAR isoforms in variouscardiovascular pathologies and highlight how therapeutic activationof PPARs may prove beneficial in preventing the development andprogression of CVD.

2.1. Atherosclerosis

Atherosclerotic vascular disease is one of the leading causes ofmortality in thewesternworld. It is principally an inflammatory diseasecharacterised by high plasma concentrations of cholesterol, particularlyin the form of LDL. As elevated circulating lipids have long beenestablished as the principal risk factor for the development ofatherosclerosis, it was originally thought to be a process mainlyconsisting of the accumulation of lipidswithin the arterywall. However,it is now known to be a much more complex and multifaceted disease.

Atherosclerotic lesions occur in large andmedium-sized arteries asa result of increased lipid levels, hypertension, increased free radicals(e.g. from smoking) and diabetes. Their formation is triggered byendothelial cell activation and dysfunction causing the release ofvasoactive molecules and cytokines, which stimulate an inflammatoryresponse and recruitment/migration of leukocytes into the arterialwall (Ross, 1999). Leukocyte migration relies on the interactionbetween endothelial cell adhesion molecules, such as vascular celladhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1(ICAM-1), E-selectin and P-selectin, and their cognate ligands oncirculating monocytes (Faggiotto et al., 1984; Springer, 1994).Increased expression of adhesionmolecules within the atheroscleroticlesion stimulates monocyte recruitment and transmigration into thearterial intima, and accumulation of lipids and extracellular matrixmay further amplify the local inflammatory response (Van der Walet al., 1992).

Once within the subendothelial space, monocytes rapidly matureinto tissue macrophages which take up oxidised lipoproteins viascavenger receptors (Goldstein et al., 1979; Brown & Goldstein, 1990).Intracellular accumulation of cholesterol results in the characteristicformation of foam cells and stimulates macrophages to secretecytokines, growth factors and other mediators that promote smoothmuscle cell proliferation and potentiate the inflammatory response,leading to arterial remodeling (Brown & Goldstein,1983). Apoptosis ofmacrophages and smooth muscle cells then occurs, which furtherenhances cytokine release. A continuing cycle of inflammation andcell infiltration causes progressive enlargement of the plaque, whichprotrudes into the arterial lumen blocking normal blood flow.Eventually, the plaque ruptures due to degradation by macrophage-induced matrix metalloproteinases (MMPs) and hydrolytic enzymes,resulting in thrombus formation and tissue infarction (Libby et al.,1996; Ross, 1999). The combined influence of lipid dysregulation andinflammation in atherogenesis strongly implies that PPARs, whichpositively influence both processes, may play a beneficial role inattenuating the development of this disease.

2.1.1. PPARα in atherosclerosisEndothelial cells (Inoue et al., 1998), vascular smooth muscle cells

(Staels et al., 1998) and monocytes/macrophages (Chinetti et al.,1998) are all known to express PPARα. In atherosclerosis, activation ofPPARα in these cells acts to reduce leukocyte recruitment, celladhesion, inflammation and injury. Endothelial activation of PPARαhas been demonstrated to downregulate cytokine-induced genes,such as VCAM-1 and tissue factor, and to inhibit the release of

monocytic chemotactic protein-1 (MCP-1), resulting in reducedinflammatory cell adhesion and attenuation of atheroma develop-ment (Marx et al., 1999; Marx et al., 2000). A conflicting studyreported that PPARα activation increased production of MCP-1 fromendothelial cells, suggesting a pro-inflammatory role for PPARα (Leeet al., 2000). However, the consensus from the majority of studiesexamining the endothelial actions of PPARα agonists appears to bethat PPARα stimulation exerts positive anti-inflammatory effects.

In addition to inhibiting the inflammatory response, PPARαagonists can also modify the release of vasoactive mediators, such asendothelin-1 (ET-1) (Delerive et al., 1999a) and nitric oxide (NO)(Goya et al., 2004) from the endothelium, to favour vasodilatation. It islikely that ET-1 is involved in atherogenesis as it is capable of inducingboth vascular smooth muscle cell proliferation and endothelial celladhesion molecules (McCarron et al., 1993) and also exerts chemo-tactic properties on monocytes (Achmad & Rao, 1992). Indeed, ET-1 ishighly expressed in atherosclerotic lesions and inhibition of ET-1 byPPARα agonists not only improves endothelial function but alsoreduces inflammation (Jones et al., 1996).

In vascular smooth muscle cells the anti-inflammatory actions ofPPARα can be demonstrated by PPARα agonist-induced inhibition ofinterleukin-1 (IL-1)-stimulated IL-6 production, prostaglandin synth-esis and COX-2 induction, effects which have been shown to occursecondary to downregulation of NF-κB and induction of p38MAPK-dependent apoptosis (Chinetti et al., 1998; Staels et al., 1998; Diepet al., 2000). PPARα activators have also been found to attenuateatherosclerotic vascular remodeling by inhibiting smooth muscle cellproliferation and migration (Delerive et al., 1999b). Furthermore,vascular smooth muscle cell migration and atherogenic plaquedestabilisation may be prevented by PPARα-dependent inhibition ofmacrophage MMP-9 expression (Marx et al., 1998; Shu et al., 2000).

Activated PPARα not only influences vascular inflammation, reactiv-ity and remodeling, but can also positively alter macrophage lipidhandling within the plaque itself. PPARα activation has been shown toreduce macrophage triglyceride accumulation and to promote redis-tribution of cholesterol from intracellular stores to the plasmamembrane, making it available for HDL-dependent efflux and reversetransport (Chinetti et al., 2001;Haraguchi et al., 2003; Chinetti-Gbaguidiet al., 2005b). In human macrophages, PPARα-mediated inhibition oflipoprotein lipase secretion results in reduced uptake of glycatedlipoprotein by these cells (Gbaguidi et al., 2002). In addition tomodifying macrophage cholesterol transport, PPARα can also inducenicotinamide adenosine dinucleotide phosphate (NADPH) oxidase-dependent reactive oxygen species (ROS) production, stimulatingmodification of LDL and enabling it to act as a PPARα ligand to furtherinhibit the induction of inflammatory mediators (Teissier et al., 2004).

Despite the overwhelming evidence supporting a beneficial rolefor PPARα in atherosclerosis, preliminary studies in PPARα null micesuggest that these animals are actually protected against diseasedevelopment (Tordjman et al., 2001; Tordjman et al., 2007). However,it is possible that these conflicting findings may not have been relatedto the absence of PPARα, but to unintended disruption of one or moreother genes (Yagil & Yagil, 2007). Further research is needed to resolvethis issue and confirm the protective role of PPARα in atherosclerosis.

2.1.2. PPARγ and atherosclerosisPPARγ has a similar vascular profile to PPARα, with significant

expression in endothelial cells (Satoh et al., 1999), smooth musclecells (Law et al., 2000) and monocytes/macrophages (Ricote et al.,1998b), and has many similar actions. Significant levels of PPARγ havebeen found in atherosclerotic lesions and its activation reducesmonocyte recruitment by the plaque (Marx et al., 1998). In endothelialcells, PPARγ activation has several beneficial actions on the inflam-matory response, including inhibition of TNFα and MCP-1 andattenuation of TNFα-induced expression of VCAM-1 and ICAM-1(Lee et al., 2000; Pasceri et al., 2000; Bruemmer et al., 2005). Like


PPARα, PPARγ also inhibits endothelial ET-1 production (Deleriveet al., 1999a) and stimulates NO release (Calnek et al., 2003), resultingin both vasodilatation and improved endothelial cell function. Inmacrophages, PPARγ agonists have been demonstrated to bothincrease PPARγ expression and inhibit MMP synthesis (Ricote et al.,1999), which contributes to their inhibitory effects on smooth musclecell proliferation. In addition, PPARγ ligands are known to inhibitmonocyte/macrophage production of other inflammatory cytokines,such as IL-6, IL-1β and TNFα, by decreasing the activity oftranscription factors, such as NF-κB (Jiang et al., 1998). In vascularsmooth muscle, PPARγ agonists also attenuate cell migration andproliferation (Law et al., 2000). Supportive evidence for a beneficialanti-inflammatory role of PPARγ in atherosclerosis is provided by astudy using an experimental mouse model, in which PPARγ agonistswere found to limit intimal hyperplasia and reduce lesion size andinflammation (Law et al., 1996).

Although the majority of studies support a beneficial effect ofPPARγ in atherogenesis, some investigators have suggested thatPPARγ may be deleterious in this situation. PPARγ has been found tostimulate genes involved in cholesterol uptake by macrophages, suchas CD36, and this process may be accentuated by further activation ofPPARγ by oxidised LDL (Nagy et al., 1998; Han et al., 2000). Thisimplies that PPARγ may promote foam cell formation; however,macrophage cholesterol content is not increased by PPARγ agonists inthe presence of acelytated LDL (Chinetti et al., 2001). Furthermore, ithas been demonstrated that PPARγ ligands can significantly inhibitthe development of atherosclerosis, in spite of elevated levels of CD36in the arterial wall (Li et al., 2000). Activated PPARγ has been shown toreduce macrophage triglyceride accumulation, lipoprotein secretionand glycated lipoprotein uptake, whilst enhancing HDL-dependentcholesterol efflux and reverse cholesterol transport (Akiyama et al.,2002; Gbaguidi et al., 2002; Haraguchi et al., 2003). These studies addfurther complexity to an already complicated picture; how can PPARγactivation increase CD36 in the absence of a concomitant increase inmacrophage LDL? The unified model (Zhang & Chawla, 2004) linksthese two conflicting arguments by suggesting that PPARγ reducesaccumulation of atherogenic oxidised LDL in the vessel wall byincreasing both macrophage uptake and efflux via upregulation ofCD36. In light of all available evidence, this theory seems to be themost plausible and supports the beneficial effects of PPARγ inatherosclerosis. A recent study by Babaev et al. (2005) employinggene-modified mice provides additional evidence to support thesuggestion that PPARγ-mediated immune cell modulation is bene-ficial in atherosclerosis. In this study macrophage-specific deletion ofPPARγ resulted in a marked increase in atherosclerosis developmentsuggesting that PPARγ-mediated macrophage activation is protectivein this pathology. Recent studies have subsequently revealed theimportance of the PPARγ as a key regulator of macrophage activityand function (Majai et al., 2007; Odegaard et al., 2007). Furthermore,in human atherosclerotic lesions PPARγ activation has been reportedto promote differentiation of proatherogenic M1 macrophages into analternative anti-inflammatory phenotype, M2, which could protectagainst the development of atherosclerosis (Bouhlel et al., 2007). Adefinitive role for PPARγ in atherogenesis could potentially beestablished with further studies in gene-modified mice such as theglobal PPARγ−/− or the endothelial cell-specific PPARγ−/−. Devel-opment of a vascular smooth muscle cell-specific PPARγ−/− mousewould also significantly aid the identification of the role of PPARγ inatherosclerosis (Duan et al., 2008).

2.1.3. PPARδ and atherosclerosisThe ubiquitous nature of PPARδ expression suggests that its

activation may play a role in the development of atherosclerosis.Indeed, recent research has extended beyond the more establishedeffects of PPARα and γ to begin to focus on PPARδ, which also appearsto exert beneficial actions on atherogenesis. In a mouse model of

atherosclerosis, PPARδ activation has been found to decrease expres-sion of MCP-1, ICAM-1 and inflammatory cytokines and to attenuatedisease development (Li et al., 2004; Graham et al., 2005). In themacrophage, PPARδ activation reduces circulating levels of pro-inflammatory cytokines and TNFα expression and has a positive effecton lipid handling by promoting cholesterol efflux, reverse cholesteroltransport and fatty acid catabolism (Oliver et al., 2001; Graham et al.,2005; Lee et al., 2006). Early work therefore suggests that activation ofPPARδ may be of potential therapeutic benefit in the treatment ofatherosclerosis. However, more detailed studies are required in orderto define its precise role in disease development and progression.

2.2. Hypertension

Chronic hypertension is a primary risk factor for CVD, particularlyatherosclerosis and heart failure (Zahradka, 2007). Despite improvedmedical treatments, its incidence is rapidly increasing and is set to reachepidemic proportions. Several factors influence the development ofhypertension, including age, gender, the existence of associatedconditions such as diabetes and obesity, and lifestyle factors such asalcohol consumption and smoking. The development of pathologicalhypertension usually occurs secondary to endothelial dysfunction andan imbalance between vasoconstrictors, such as angiotensin II (Ang II)and ET-1, and vasodilators, such as NO (Schulman et al., 2006).Atherosclerosis itself can also cause hypertension due to protrusion ofthe lesion into the lumen, resulting in narrowing of the blood vessel,which cannot be counteracted by local vasorelaxant mechanisms (Ross,1999).

To date the role of the different PPAR isoforms in hypertensionhave been examined in a number of commonly used experimentalmodels. These include (1) the deoxyycorticosterone acetate (DOCA)-salt model, which is associated with enhanced expression ofpreproET-1; (2) the spontaneously hypertensive rat (SHR), in whicha genetic mutation results in alteration of the renin–angiotensin–aldosterone system, causing sodium retention and elevated bloodpressure in the absence of concomitant obesity and diabetes (Koboriet al., 2005); (3) chronic Ang II infusion. Interestingly, PPAR agonistshave been demonstrated to have direct vasorelaxant effects (Goyaet al., 2004), suggesting that they may hold therapeutic potential aseffective anti-hypertensive agents.

2.2.1. PPARα and hypertensionPPARα is widely expressed in all vascular cell types suggesting that

its activation may be involved in the control of blood pressure bymodulation of vascular tone. Indeed, PPARα-dependent regulation ofblood pressure has been demonstrated in each of the aforementionedexperimental models of hypertension. In Ang II-infused rats, thePPARα agonist, docosahexaenoic acid (DHA) was found to reduceblood pressure and attenuate vascular remodeling, possibly byinhibiting the development of NADPH oxidase-induced endothelialdysfunction (Diep et al., 2002a). In the same experimental model, thePPARα agonist, fenofibrate-induced a significant decrease in bloodpressure which was associated with reduced expression of vascularinflammatory mediators (Diep et al., 2004). However, in the DOCA-salt model of hypertension, fenofibrate failed to normalise meanarterial blood pressure, despite PPARα activation causing a significantreduction in NADPH oxidase-dependent superoxide generation(Iglarz et al., 2003). Interestingly, clofibrate was also found to inhibitNADPH oxidase activity in this model, but in contrast to fenofibrate,significantly reduced blood pressure, an effect whichwas attributed toinhibition of endothelial ET-1 production (Delerive et al., 1999a;Newaz et al., 2005). In the SHR, increased PPARα expression has beenfound in both whole blood vessels and cultured vascular smoothmuscle cells from these animals (Diep & Schiffrin, 2001). In thismodel, chronic PPARα activation with fenofibrate has also beendemonstrated to be associated with a reduction in systolic blood


pressure (Li et al., 2008), although other investigators have failed toreport anti-hypertensive effects (Wu et al., 2004).

Studies using PPARα−/− mice have produced conflicting findings inregard to its role in blood pressure regulation. Deletion of PPARαhas been shown to significantly increase (Newaz et al., 2005), decrease(Guellich et al., 2007) andhaveno significant effect (Loichot et al., 2006)on systolic blood pressure compared with wild-type controls. Interest-ingly, Newaz et al. (2005) found that the increased blood pressure intheir PPARα−/− mice could be abolished by the NO synthase (NOS)inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME), suggesting thatPPARα may modulate endothelial NO production (Goya et al., 2004).

2.2.2. PPARγ and hypertensionPPARγ is expressed in vascular smooth muscle and endothelial

cells, and glitazone-induced activation has been found to exert bloodpressure-lowering effects in insulin-resistant fatty Zucker rats,although the mechanisms of action were unclear (Walker et al.,1999). In Ang II-induced hypertension, the PPARγ agonists, pioglita-zone and rosiglitazone caused a significant decrease in blood pressure,in addition to beneficial actions on cell growth, endothelial functionand vascular inflammation. These effects were found to be mediatedvia inhibition of DNA synthesis, NF-κB activity, and endothelial/platelet adhesion molecule expression (Diep et al., 2002b). It has alsobeen suggested that the apparent hypotensive effects of PPARγagonists in this model may result from downregulation of the Ang IItype 1 receptor (Sugawara et al., 2001). More recently, investigatorshave begun to examine how PPARγ agonists directly affect the renin–angiotensin system, with initial studies suggesting that PPARγactivation stimulates renin gene expression (Todorov et al., 2007).This could potentially lead to increased Ang II production with aresultant increase in blood pressure, but is contradictory to thebeneficial hypotensive effects previously observed with PPARγagonists. One possible explanation could be that a delicate balanceexists in the vasculature between the beneficial effects of PPARγ andthe deleterious influence of the renin–angiotensin system, so tippingthe balance in favour of the latter could potentially be a key factorunderlying the development of hypertension (Weatherford et al.,2007).

In DOCA-salt hypertensive rats, mean arterial blood pressure wasalso normalised by administration of rosiglitazone, an effect whichwas not seen with the PPARα agonist, fenofibrate (Iglarz et al., 2003).However, both PPAR activators were found to attenuate the increasedpreproET-1 expression and concentric hypertrophy which are char-acteristic of this model. Although only the PPARγ agonist preventedhypertensive endothelial dysfunction, both agonists were found tosignificantly reduce ROS production, implying that this is not theprimary mechanism underlying impaired vascular function in thismodel. PPARγ has also been shown to antagonise endothelial ET-1secretion, so its anti-hypertensive effects in this ET-1-dependentmodel of hypertension are maybe not surprising (Satoh et al., 1999).

In the SHR, the PPARγ agonist, pioglitazone has been demonstratedto lower blood pressure (Verma et al., 1998; Grinsell et al., 2000).However, when these animals were treated with a NOS inhibitor, L-NAME, effects on blood pressure, metabolism and serum NO levelswere no longer evident, although pioglitazone did prevent vascularinflammation and the development of atherosclerosis (Ishibashi et al.,2002). Furthermore, administration of ciglitazone to SHRs has beenfound to ameliorate vascular endothelial dysfunction via increasedNOS activity (Smiley et al., 2004), supporting the suggestion thatstimulation of NO production is essential to this PPARγ-mediatedreduction of blood pressure.

It has previously been suggested that downregulation of PPARγmay be responsible for the vascular proliferation, migration, inflam-mation and fibrosis found in the SHR (Schiffrin, 2005). Indeed,vascular expression of PPARγ proteins was found to be reduced at21 weeks in this model, compared to age-matched wild-type animals,

although at a younger age (5–13 weeks) no significant difference wasdetected (Wu et al., 2004). Treatment with the PPARγ agonist,rosiglitazone from 5–13 weeks, attenuated the subsequent develop-ment of, hypertension, although PPARα activation had no significanteffect (Wu et al., 2004). However, PPARγ activation in the SHR, whilstconferring beneficial effects on blood pressure, was also found to beassociated with left ventricular (LV) hypertrophy. In contrast to thisstudy, there are previous reports of increased vascular expression ofboth PPARα and γ in SHR's at 16 weeks (Diep & Schiffrin, 2001), so theprecise role of PPARγ in this model is far from certain. Taken together,it appears that PPARγ attenuates the development of hypertension viaa mechanism involving increased NO production, reduced ET-1secretion and inhibition of NADPH oxidase. However, the potentialclinical benefit may be limited by side effects such as weight gain,oedema, headache and visual disturbances which are commonlyassociated with PPARγ receptor agonists.

The effect of PPARγ deletion on blood pressure has recently beenexamined in the newly developed generalised PPARγ−/− mouse, inwhich the embryonic lethality of global PPARγ deletion was rescuedby preserving trophoblastic PPARγ expression (Duan et al., 2007).These mice were found to exhibit hypotension, which was resistant tocorrection by high salt loading. Further ex vivo studies revealed thatthe vasculature of these animals was more sensitive to endothelium-dependent relaxation caused by muscarinic stimulation (in theabsence of changes in endothelial NOS expression or phosphoryla-tion) and less responsive to α-adrenergic contractile agents, leadingthe authors to conclude that the hypotension observed in thesePPARγ−/− mice occurred via a mechanism involving increasedvascular relaxation. Whilst previous studies have reported PPARγactivation to also cause hypotension (Grinsell et al., 2000; Duan et al.,2007), this was found to occur in the presence of increased endothelialNOS expression which was not observed in vessels from generalisedPPARγ−/−mice. Interestingly, this may suggest that PPAR is capable ofmodulating blood pressure via divergent mechanisms, although moredetailed studies in the generalised PPARγ−/− are clearly required tofurther investigate this possibility.

2.2.3. PPARδ and hypertensionDespite the recent discovery of specific PPARδ ligands, such as

L165041 and GW0742X, the role of PPARδ in the regulation of vasculartone and development of hypertension remains unknown.

2.3. Cardiac ischaemia–reperfusion

Chronic heart failure affects up to 2% of the adult population in thewestern world, the most common cause of which is myocardialinfarction (MI). MI results from coronary artery occlusion, usuallyoccurring after atherosclerotic plaque rupture. This causes ischaemiaof the cardiac muscle, the severity of which varies depending on thelocation of the occlusion within the coronary vasculature. Prolongedischaemia leads to cardiomyocyte death which is followed by a seriesof structural and functional alterations in the viable myocardium,known as cardiac remodeling. In particular, adaptive changes in theextracellular matrix and in cardiomyocyte biology occur, which areinitially able to maintain contractile function. However, progressivecardiac remodeling leads to chamber dilatation, contractile dysfunc-tion and ultimately heart failure (Snghedauw, 1999). The resultantmetabolic changes may also lead to the development of potentiallylife-threatening arrhythmias. Myocardial reperfusion is the standardfirst-line treatment in acute MI, aiming to restore blood flow to theischaemic myocardium and promote tissue survival. However,reperfusion itself has been found to exacerbate ischaemic damage,causing further depression of cardiac function (Piper et al., 2003).Various experimental models have been employed to study eithermyocardial ischaemia with subsequent reperfusion or cardiac remo-deling associated with chronic MI.


Infiltration of neutrophils and macrophages is known to enhancethe inflammatory response to myocardial ischaemia (Frangogianniset al., 2002) and in combination with rapid accumulation of ROSwithin the ischaemic zone can lead to tissue necrosis upon reperfusion(Li et al., 1999). This is further amplified by activation of redox-sensitive transcription factors, such as NF-κB and AP-1, which controlthe expression of pro-inflammatory mediators, such as IL-12 andTNFα. Indeed, in an experimental rat model, inhibition of NF-κB hasbeen demonstrated to reduce reperfusion injury after a brief period ofischaemia (Onai et al., 2004). Furthermore, upregulation of AP-1 hasbeen observed in cardiomyocytes in the presence of increased levels ofROS (Aggeli et al., 2006), such as those observed during ischaemia andreperfusion, suggesting that this transcription factor may be involvedin the pathogenesis of ischaemia and subsequent reperfusion.Interestingly, PPARs have been shown to exert their anti-inflammatoryeffects via NF-κB and AP-1 inhibition, suggesting a potential mechan-ism by which agonists of these receptors may be beneficial inattenuating ischaemia–reperfusion injury (Chinetti et al., 1998;Dragomir et al., 2006; Smeets et al., 2007).

2.3.1. PPARα and cardiac ischaemia–reperfusionPPARα is abundantly expressed in the heart, where it plays an

important role in the regulation of fatty acid oxidation by inducing theexpression of genes encoding proteins involved in fatty acid uptakeand metabolism. Under normal physiological conditions, fatty acidsact as the primary energy source for adult cardiomyocytes. In theischaemic myocardium and after reperfusion PPARα has been foundto be downregulated, although it is unclear whether this is a beneficialor detrimental adaptation (Dewald et al., 2005). In an attempt toclarify the precise role of PPARα in ischaemia–reperfusion andestablish whether PPARα ligands may be beneficial in its treatment,many studies have examined their effects in various experimentalmodels of ischaemia and/or reperfusion.

Overall, PPARα appears to have a beneficial effect in ischaemia–reperfusion. In an in vivo rat model of ischaemia–reperfusion, infusionof the PPARα agonist, Wy 14,643 prior to coronary artery occlusionresulted in a significant decrease in infarct size, which was associatedwith increased myocardial contractility (Wayman et al., 2002a;Bulhak et al., 2006), suggesting that PPARα activation may attenuatethe depression of cardiac function that typically occurs duringreperfusion (Yeh et al., 2006). The cardioprotective effect of PPARαactivation has been linked to inhibition of the NF-κB pathway (Yueet al., 2003; Yeh et al., 2006) and the associated decrease in expressionof inflammatory mediators. Another PPARα agonist, GW7647 has alsobeen demonstrated to significantly reduce infarct size in a mousemodel of ischaemia–reperfusion (Yue et al., 2003). This positive effecton ischaemia–reperfusion was abolished in PPARα−/− mice, suggest-ing that it occurs through direct activation of the receptor. Adminis-tration of the fibrates, clofibrate (Wayman et al., 2002b; Tian et al.,2006) and fenofibrate (Tabernero et al., 2002) have also been shownto have beneficial effects in ischaemia–reperfusion both ex vivo and invivo, adding further support to the idea that PPARα activation may becardioprotective.

Despite the widely reported beneficial effects of Wy 14,643 inischaemia–reperfusion, a conflicting study has demonstrated that it isassociated with negative effects in an in vivo mouse model ofrepetitive ischaemia–reperfusion (Dewald et al., 2005). However,significant differences between the time course, metabolic effects andmechanisms underlying ischaemic injury in this model comparedwith the single ischaemic insult employed by most studies, mayaccount for the lack of effect of the PPARα agonist. Findings fromPPARα gene-modified mice are also somewhat contradictory. Forexample, whereas the presence of PPARα has been found to bebeneficial in preserving cardiac function in ischaemia–reperfusion(Tabernero et al., 2002), isolated perfused hearts from PPARα−/−

mice demonstrated improved function after ischaemia (Panagia et al.,

2005; Sambandam et al., 2006) and those from animals overexpres-sing PPARα exhibited reduced recovery (Sambandam et al., 2006).Furthermore, some investigators have demonstrated a positive effectof PPARα ligands against hypoxic damage (Wayman et al., 2002a,b;Bulhak et al., 2006), whilst others have reported that they have nosignificant effect on (Aasum et al., 2003) or are deleterious to(Sambandam et al., 2006) cardiac functional recovery after ischaemia.A likely explanation for these conflicting findings appears to be thechoice of experimental model, as in general, in vivo studies havetended to show PPARα agonists to exert cardioprotective effects,whereas ex vivo studies have produced varying results. The isolatedheart preparation, for example, is not subject to the neurohumoralinfluences experienced in vivo and the use of pharmacological PPARαagonists versus PPARα gene-modified animals may also contribute tothe diversity of experimental findings.

2.3.2. PPARγ and cardiac ischaemia–reperfusionAs PPARγ is predominantly expressed in adipocytes, the majority

of studies have tended to focus on its predominant role in lipidmetabolism. As such, the precise physiological role of PPARγ in themyocardium has yet to be fully established. PPARγ has, however, beenfound to be expressed in rat heart and PPARγ agonists have beenshown to reduce myocardial infarct size (Wayman et al., 2002b).Overall, the findings from studies on the effects of PPARγ activation inischaemia–reperfusion are much more consistent than those foundwith PPARα, suggesting that PPARγ agonists may be of greaterpotential therapeutic benefit in this setting.

Studies employing chemically different ligands to activate PPARγ,such as the thiazolidinediones (rosiglitazone, troglitazone, pioglita-zone and ciglitazone) and prostaglandins (15d-PGJ2 and PGA1) havedemonstrated significant reduction in infarct size and improvement ofmyocardial function. Rosiglitazone has been shown to reduce infarctsize in various in vivo (Yue et al., 2001; Wayman et al., 2002b; Liuet al., 2004; Molavi et al., 2006) and ex vivo (Khandoudi et al., 2002;Sidell et al., 2002) experimental models of ischaemia–reperfusion.Furthermore, significant recovery of LV developed pressure has beenobserved during post-ischaemic reperfusion after rosiglitazone treat-ment (Gonon et al., 2007). Pioglitazone and ciglitazone have beenfound to exert similar positive effects to rosiglitazone in all models ofischaemia–reperfusion, causing significant infarct size reduction andimproved cardiac function (Wayman et al., 2002b; Ito et al., 2003;Sivarajah et al., 2005; Wynne et al., 2005; Zingarelli et al., 2007). In anin vivo pig model of myocardial ischaemia–reperfusion, the PPARγagonist troglitazone was found to improve recovery of LV systolic anddiastolic function (Zhu et al., 2000), a finding which is supported bysimilar studies using other animal models (Shimabukuro et al., 1996;Lee & Chou, 2003). In addition, the high affinity endogenous ligand forPPARγ, 15d-PGJ2 (which also has PPARγ-independent actions; Kaplanet al., 2007), has been found to reduce infarct size and improve cardiacfunctional recovery after ischaemia, which suggests that the effects ofPPARγ agonists are mediated via a direct action on the receptor.Indeed, inhibition of PPARγ with the specific receptor antagonist,GW9662, results in a significant increase in infarct size followingischaemia–reperfusion (Sivarajah et al., 2005). However, in contrast tothe majority of evidence implying that thiazolidinediones arebeneficial in ischaemia–reperfusion, troglitazone was shown tosignificantly increase the incidence of ventricular arrhythmias duringa period of 90 min ischaemia followed by the same duration ofreperfusion in an in vivo pig model (Xu et al., 2003).

Several different mechanisms have been suggested to mediate thecardioprotective effects of PPARγ, such as inhibition of NF-κB,(Wayman et al., 2002b), reduced infiltration of leukocytes (Yueet al, 2001; Ito et al., 2003) and inhibition of apoptosis (Liu et al.,2004). PPARγ agonists have been demonstrated to rapidly inducetheir cardioprotective effects, within minutes of administration, anda bolus dose of ligand prior to ischaemia is just as effective in


attenuating myocardial injury as continual infusion. These observa-tions suggest that the beneficial effects of PPARγ activation inischaemia–reperfusion are not mediated through longer-term altera-tions in gene expression, although they may occur secondary to theiranti-inflammatory actions.

Few studies have examined the effects of PPAR (α or γ) activationin experimental models of chronic MI, in which permanent coronaryartery occlusion leads to cardiomyocyte death within the ischemiczone and remodeling of the viable myocardium. Those which havedone have produced conflicting findings. For example, the PPARαagonist, fenofibrate has been found to accelerate the development ofLV hypertrophy (Morgan et al., 2006), whereas the PPARγ agonist,rosiglitazone has been reported to both increase mortality (Lygateet al., 2003) and improvemyocardial remodeling (Geng et al., 2006). Itis possible that these inconsistent results may be due to differences inexperimental study design. Nonetheless, significant further research isrequired in order to delineate the precise role of PPARs in chronicischaemic remodeling.

2.3.3. PPARδ and cardiac ischaemia–reperfusionDespite the preponderance of evidence suggesting that activation

of PPARα and γ is cardioprotective in ischaemia–reperfusion, the roleof PPARδ has yet to be established.

2.4. Cardiac hypertrophy

LV hypertrophy is an independent risk factor for heart failure,arrhythmia and sudden death and is one of themost potent predictorsof adverse cardiovascular outcomes in hypertensive patients (Healey &Connolly, 2003; Gradman & Alfayoumi, 2006). It is characterised bymaladaptive changes in myocardial structure and function, which arecollectively known as cardiac remodeling. The heart initially compen-sates for the increasedwall stress by undergoing significant alterationsin cardiomyocyte biology and in the extracellular matrix. However,progressive LV hypertrophy combined with loss of collagen cross-linking and myocyte slippage causes increased wall stress leading tocardiac chamber dilatation, contractile dysfunction and ultimatelydecompensated congestive heart failure (Snghedauw, 1999; Frey &Olsen, 2003). Despite improved clinical management of hypertensionwith agents such as angiotensin-converting enzyme (ACE) inhibitorsand β-blockers, which attenuate cardiac remodeling and havemorbidity/mortality benefits, there remains a substantial incidenceof heart failure even in optimally-treated patients (Francis & Young,2001). A detailed understanding of the complex regulatory mechan-isms underlying the pathogenesis of cardiac remodeling is thereforeessential to inform the development of more effective treatments.

The development of cardiac hypertrophy is influenced by severalfactors such as age, weight and obesity. It may also develop in theabsence of increases in blood pressure in patients with obesity anddiabetes, where the heart acts to compensate for the loss of functionalheart muscle through the effects of disease and injury (Otto et al.,2004). Changes in structure and function of the heart are mediated bya variety of mechanical, neuronal and hormonal factors.

2.4.1. PPARα and cardiac hypertrophyIn the normal adult heart, fatty acids serve as the chief energy

substrate (Taegtmeyer, 1994) as they are more efficient, providing agreater yield of ATP compared to either glucose or lactate. Circulatingfatty acids are transported into the cardiomyocyte, where they aremetabolised via mitochondrial β-oxidation. In contrast, the fetal heartrelies primarily on glucose and lactate due to its relatively hypoxicenvironment, as glycolytic production of ATP is more oxygen efficientthan fatty acidmetabolism. In the neonatal heart, the capacity for fattyacid oxidation rapidly increases in parallel with mitochondrialproliferation within the cardiomyocyte, establishing fatty acids asthe primary source of ATP.

PPARα activation in the heart stimulates upregulation of genescontrollingmitochondrial fatty acid uptake, which results in increasedfatty acid metabolism and generation of ATP (Brandt et al., 1998; vander Lee et al., 2000a,b; Vosper et al., 2002). In the hypertensive heart,the increased demands on the myocardium trigger significantalterations in energy metabolism. Both clinical and experimentalstudies in hypertrophied and failing hearts demonstrate a decrease inthe expression of genes involved in fatty acid oxidation, with anincrease in glucose oxidation, although in this setting the energyprovided by this alternative source does not correspond to thatpreviously supplied via fatty acid metabolism (Bishop & Altschuld,1970; Christie & Rodgers, 1994; Takeyama et al., 1995; Sack et al.,1996). This reversion to the fetal genotype is a characteristic feature ofcardiac hypertrophy, and occurs not only in genes involved inoxidative metabolism, but also in those controlling other aspects ofcardiomyocyte biology. As PPARα is the principal regulator ofmyocardial fatty acid oxidation, it seems likely that the decreasedexpression of genes involved in fatty acid oxidation as observed incardiac hypertrophy may be a consequence of altered PPARα activityor expression.

PPARα was initially implicated in cardiac hypertrophy whenchildren with congenital defects in fatty acid oxidation were foundto develop the disease (Kelly & Strauss, 1994). In adults, variations inthe genes encoding for PPARα have also been shown to influence bothphysiological and pathological hypertrophic growth of the myocar-dium (Jamshidi et al., 2002). In a mouse model of pressure overload-induced by transverse aortic constriction, Barger et al. (2000)reported downregulation of PPARα and several of its target genes inparallel with significant increases in morphometric hypertrophy andatrial natriuretic factor (ANF) expression, suggesting that down-regulation of PPARα may be responsible for reversion to the fetalmetabolic genotype in the hypertrophied myocardium.

Whether the altered activity of PPARα in hypertrophy is adaptiveor indeed related to myocardial pathology has been the subject ofintense debate. In pressure overload-induced cardiac hypertrophy,reversion to the fetal genotype is initially thought to be an adaptiveand beneficial response (Frey & Olsen, 2002), as glucose oxidationsubstitutes for fatty acid metabolism to reduce oxygen consumption.However, with progressive hypertrophy, reduced ATP production viathe glucose oxidation pathway, results in cardiac contractile dysfunc-tion and myocardial lipid accumulation and toxicity (Barger & Kelly,2000). This suggests that although downregulation of PPARα may beinitially beneficial, it may also be maladaptive during the decom-pensated stage of cardiac hypertrophy.

Many studies have attempted to clarify the precise role of PPARαin cardiac hypertrophy, but conflicting findings have only served tofurther confuse the issue. An early study employing a rat model ofascending aortic constriction for 7 days found that pharmacologicalreactivation of PPARα with Wy 14,643 had no significant effect onmorphological hypertrophy or induction of ANF (Young et al., 2001).Surprisingly, reactivation of PPARα in the hypertrophied heart alsoled to severe depression of cardiac power and efficiency assessed exvivo, suggesting that downregulation of PPARα may be a necessaryadaptation to maintain myocardial function. Indeed, administrationof Wy 14,643 was also found to cause a substantial decline inglucose oxidation, rather than the anticipated increase in fatty acidoxidation, which would result in myocardial energy starvation, thusaccounting for the observed cardiac dysfunction (Young et al.,2001). In another study, normal rats fed with Wy 14,643 for26 weeks were found to develop significant morphometric cardiachypertrophy, indicating that PPARα activation alone can act as ahypertrophic stimulus (Hamano et al., 2001). Furthermore, the sameauthors reported that co-application of Wy 14,643 and clofibrate to arat cardiomyocyte cell line significantly increased transcription ofthe pro-hypertropic marker gene, myosin light chain-2, supportingtheir in vivo observation (Hamano et al., 2001). Cardiac-specific


overexpression of PPARα in mice has also been demonstrated to bedeleterious, resulting in significantly reduced myocardial glucoseoxidation. Interestingly, these mice, unlike the previously describedrat models, exhibited increased fatty acid oxidation, althoughthis was not sufficient to prevent cardiac dysfunction (Finck et al.,2002). This suggests that PPARα downregulation is beneficial, butthat overexpression of PPARα induces a complete reliance on fattyacid oxidation, leading to oxygen depletion and loss of normalfunction. However, the function of PPARα in this rather artificialsituation may not be indicative of its role at physiological expressionlevels.

Although many studies have demonstrated a negative influence ofPPARα in cardiac hypertrophy, there are an increasing number ofconflicting reports indicating that PPARα activation may actually bebeneficial in this setting. In vivo activation of PPARα by fenofibrate hasbeen found to inhibit the development of myocardial fibrosis in ratssubjected to pressure overload via inhibition of ET-1-mediatedfibroblast proliferation (Ogata et al., 2002). Fenofibrate treatmenthas also been found to attenuate the development of myocardialhypertrophy and fibrosis and to preserve in vivo contractile function inDahl salt-sensitive rats, through inhibition of NF-κB-mediatedinflammation (Ichihara et al., 2006). These effects were thought tooccur via inhibition of the inflammatory response through down-regulation of NF-κB, and deactivation of redox-regulated transcriptionfactors and the subsequent reduction in ROS production. In DOCA-salthypertensive rats overexpressing ET-1, Iglarz et al. (2003) confirmedthat fenofibrate administration significantly attenuated cardiac fibro-sis and remodeling, which was associated with decreased myocardialinflammation. Activation of PPARα by fenofibrate was also shown toinhibit ET-1-induced cardiac hypertrophy in isolated rat cardiomyo-cytes (Li et al., 2007), adding further weight to the suggestion thatfenofibrate-induced PPARα activation inhibits cardiac hypertrophy.Furthermore, in vitro studies using rat neonatal cardiomyocytes havereported fenofibrate to inhibit ET-1-induced hypertrophy and proteinsynthesis (Liang et al., 2003; Irukayama-Tomobe et al., 2004) and Wy14,643 to inhibit hypertrophy via inhibition of NF-κB (Smeets et al.,2008a).

Fig. 4. Role of ROS and PPARα in the development of cardiac hypertrophy. The productionintracellular responses which eventually lead to the development of myocardial hypertrophyof PPARα, leading to decreased fatty acid oxidation and glucose metabolism which is chara

Studies using PPARα−/− mice have predominantly shown thatabsence of the receptor is detrimental to cardiac function. A recentstudy by Smeets et al. (2008b) demonstrated that PPARα−/− micesubjected to chronic pressure overload developed significantly morepronounced cardiac hypertrophy and contractile dysfunction com-pared to wild-type controls. Other groups using the same micehave demonstrated that the absence of PPARα results in reducedmyocardial fibrosis and ex vivo contractile dysfunction in isolatedhearts, which was more susceptible to further deterioration but couldbe rescued by increasing cardiac glucose utilisation (Luptak et al.,2005; Loichot et al., 2006). It has also been reported that fenofibratetreatment further exacerbates cardiac hypertrophy, fibrosis andremodeling in PPARα−/− mice subjected to chronic pressure over-load, whilst reducing remodeling inwild-type animals, indicating thatPPARα agonists may exert deleterious effects which are independentof receptor activation (Duhaney et al., 2007). This may also explain thenegative findings in respect to pharmacological PPARα reactivationwithWy 14,643 in the hypertrophiedmyocardium. As all studies usingfenofibrate in wild-type animals have reported positive effects oncardiac hypertrophy, this suggests that the beneficial actions of PPARαactivation may outweigh any negative receptor-independent effects.

The link between PPARα activation and inhibition of ROS whichhas been borne out by many of the pharmacological studies issupported by the findings of another study in PPARα−/− mice, inwhich myocardial expression of the ROS-scavenging enzyme, super-oxide dismutase, was found to be significantly reduced and associatedwith oxidative damage to cardiac myosin. The authors suggested thatdecreased superoxide dismutase activity may lead to elevatedmyocardial ROS production, which could be responsible for theimpaired cardiac contractile function observed in PPARα−/− mice(Guellich et al., 2007). The role of ROS and the downregulation ofPPARα in hypertrophy development are illustrated in Fig. 4.

Taken together, it appears that PPARα downregulation or absenceof the receptor is detrimental in cardiac hypertrophy. Pharmacologicalreactivation of PPARα may attenuate the progression of hypertrophyand associated contractile dysfunction, although a more completeunderstanding of the receptor-independent actions of PPARα agonists

of ROS and downregulation of PPARα (as a result of hypertension) initiates a series ofand remodeling. It has been suggested that ROS may also stimulate the downregulationcteristic of cardiac hypertrophy.


is required before their potential therapeutic benefit can be accuratelyassessed.

2.4.2. PPARγ and cardiac hypertrophySimilar to PPARα, the precise involvement of PPARγ in cardiac

hypertrophy remains somewhat controversial. PPARγ is known to beexpressed at a low level in the heart (Escher & Wahli et al., 2000;Wayman et al., 2002b). Nonetheless, the majority of studies investi-gating the effects of PPARγ agonists in cardiac hypertrophy suggestthat they may play a protective role, although the mechanismsunderlying these actions are unclear. Of note, agonists for PPARγhave been found to have no significant effect on cardiomyocyteexpression of target genes involved in fatty acid oxidation (Barger &Kelly, 2000). Consistent with this finding, a study by Gilde et al. (2003)in rat neonatal cardiomyocytes revealed that the rate of fatty acidoxidation significantly increased after exposure to PPARα and PPARδligands, but not to PPARγ ligands. Similarly, the fatty acid-mediatedexpression of fatty acid-handling proteins was mimicked by PPARαand PPARδ but not by PPARγ ligands. Furthermore, in adult ratcardiomyocytes activation of PPARγ had no significant effect on fattyacid metabolism but prevented cell hypertrophy, suggesting thatinactivation of PPARγ may enable the development of hypertrophy(Pellieux et al., 2007). Taken together, it appears that PPARγ may notexert its cardiac effects via regulation of myocardial metabolism.

Several studies employing various in vitro and in vivo experimentalmodels have demonstrated that PPARγ activation significantlyreduces the development of cardiac hypertrophy and fibrosis. Boththe synthetic agonists of PPARγ, the thiazolidinediones, and theendogenous activator, 15d-PGJ2, have been found to attenuatemechanical strain and ET-1-induced hypertrophy in neonatal cardi-omyocytes, respectively (Yamamoto et al., 2001; Liang et al., 2003).This effect was shown to bemediated via PPARγ-dependent inhibitionof the NF-κB pathway (Yamamoto et al., 2001) and could be reversedwith a specific PPARγ antagonist, leading to induction of the pro-hypertrophic marker gene, brain natriuretic peptide (BNP) (Liang etal., 2003). This latter observation implies that the beneficial effects ofPPARγ agonists in cardiac hypertrophy could be due to direct receptoractivation. Indeed, the heterozygous PPARγ+/−mouse has been foundto exhibit cardiac hypertrophy, which is further accentuated uponimposition of chronic pressure overload (Asakawa et al., 2002).Rosiglitazone has also been found to significantly reduce cardiacremodeling and fibrosis in DOCA-salt hypertensive rats (Iglarz et al.,2003), as has ciglitazone in a mouse model of chronic pressureoverload-induced by abdominal aortic constriction (Henderson et al.,2007). Ciglitazone also attenuated pressure overload-inducedincreases in the expression of the NADPH oxidase subunit, Nox4,suggesting a potential role for ROS in its cardioprotective actions(Henderson et al., 2007).

Despite the large amount of evidence supporting a beneficial rolefor PPARγ in cardiac hypertrophy, several studies have reportedcontradictory findings. In vivo administration of rosiglitazone wasshown to accentuate the development of cardiac hypertrophy in SHRs(Wu et al., 2004). Furthermore, chronic treatment of normal rats withboth the selective PPARγ agonist, X334, and the novel thiazolidine-dione, T-174, were found to induce cardiac hypertrophy (Arakawa etal., 2004; Edgley et al., 2006). However, in the latter study, this effectwas attributed to an increase in blood volume following T-174treatment, rather than a direct effect on the myocardium. Indeed,hypervolaemia and oedema are known to be common side effects ofthiazolidinedione treatment (Edrmann & Wilcox, 2008), which mayalso account for the hypertrophic effects observed in the other twostudies. Interestingly, rosiglitazone has been reported to inducecardiac hypertrophy in both cardiomyocyte-specific PPARγ−/− miceand wild-type littermate controls via activation of distinctly differentpathways (Duan et al., 2005), indicating that the presence of PPARγ inthe myocardium may suppress the actions of trophic stimuli, and that

PPARγ ligands could mediate their effects independently of PPARγ.This suggestion is supported by an elegant study which employed bothcardiomyocyte and macrophage-specific PPARγ−/− mice to investigatethe effect of PPARγ ligands on the development of angiotensin II(Ang II)-induced cardiac hypertrophy and fibrosis (Caglayan et al.,2008). Administration of the PPARγ agonist, pioglitazone was found topromote Ang II-induced cardiac hypertrophy in both cardiomyocyte-specific PPARγ−/− mice and wild-type littermate controls, whilstattenuating parallel increases in myocardial fibrosis, again indicatingthat PPARγ ligands may exert their cardiac effects independently ofPPARγ. Furthermore, the beneficial actions of pioglitazone on Ang II-induced fibrosis were found to be absent in macrophage-specificPPARγ−/−mice, suggesting thatmacrophage PPARγ-induced inhibitionof myocardial macrophage infiltration is critical to this effect. Previousstudies relating to the effects of PPARγ agonists on cardiac hypertrophymust therefore be interpreted with care given these PPAR-independenteffects. Nonetheless, findings from gene-modifiedmice are encouragingand suggest that PPARγ may be beneficial in preventing myocardialhypertrophy. It is possible that the future development of more specificPPARγ agonists may reveal the true role of PPARγ and unlock theirtherapeutic potential.

2.4.3. PPARδ and cardiac hypertrophyPPARδ is significantly expressed in the myocardium (Gilde et al.,

2003; Cheng et al., 2004a), where it has been reported to be involvedin the transcriptional regulation of lipid metabolism (Barger & Kelly,2000). However, to date, few studies have examined the role of PPARδin cardiac hypertrophy. Cardiomyocyte-specific PPARδ−/− mice havebeen shown to exhibit myocardial lipid accumulation, hypertrophyand heart failure with reduced survival (Cheng et al., 2004b),suggesting that PPARδ may play a crucial role in maintaining normalcardiac function. Furthermore, in vitro activation of PPARδ with bothL-165041 and GW501516 was found to inhibit phenylephrine-inducedhypertrophy of neonatal rat cardiomyocytes via inhibition of NF-κB(Planavila et al., 2005; Smeets et al., 2008a). The positive findingsfrom these preliminary studies are encouraging, but significantfurther investigation is required in order to identify the precise roleof PPARδ activation in cardiac hypertrophy.

2.5. Clinical implications

Fibrates and thiazolidinediones arewidely used in the treatment ofhyperlipidaemia and type II diabetes, respectively. Although these aretheir primary indications due to positive effects on glucose home-ostasis, lipid metabolism, atherogenic proteins, endothelial function,inflammation and thrombosis, these compounds may also be ofbenefit in other related pathologies, such as CVD (Verges, 2004).Indeed, recent attention has focussed on the potential use of PPARαagonists in the treatment of CVD, and how improvements in lipidbalance, through continued treatment with these compounds, maybeneficially affect cardiovascular morbidity and mortality. Firstgeneration fibrates, such as clofibrate, are known to be effective inlowering blood lipids with some studies revealing an associatedreduction in the incidence of cardiovascular events (Vosper et al.,2002). This observation is supported by both the Helsinki Heart Study(Frick et al., 1987) and the Veterans Affairs HDL Intervention Trial(Rubins et al., 1999), in which treatment with the second generationfibrate, gemfibrizil, for 5 years was found to result in a 34% reductionin the cardiovascular event rate and a 22% decrease in mortality,respectively. Interestingly, subjects who had elevated circulatingglucose levels and/or were overweight were found to benefit mostfrom gemfibrizil treatment (Tenkanen et al., 1995). More recently, theFenofibrate Intervention and Event Lowering in Diabetes (FIELD)study found that the incidence of non-fatal MI and cardiovascularmortality in patients with type II diabetes was not significantlydecreased by fenofibrate treatment (Keech et al., 2005). However,


secondary end points, such as stroke and vascular disease, weresignificantly reduced, although the fact that this was not associatedwith a concomitant decrease in mortality brings the overallcardiovascular benefit of long-term fenofibrate therapy into question.

PPARγ agonists have also been employed in clinical trials to examinewhether their known insulin-sensitising and anti-inflammatory actionsare beneficial in CVD. In diabetic patients, pioglitazone therapy wasfound to cause a significant reduction in all cause mortality, non-fatalMI and stroke (Dormandyet al., 2005) and to significantly reduce carotidintima/media thickness, which is used as a measure of atheroscleroticvascular remodeling (Mazzone et al., 2006). However, the potential useof PPARγ agonists in the treatment of CVD may be limited by profoundside effects. Glitazone treatment has been associated with weight gainand peripheral oedema,whichmay precipitate an increased risk of heartfailure (Lindberg & Astrup, 2007). More worryingly, a recent meta-analysis of clinical trials conducted in diabetic patients concluded thatrosiglitazone treatment conferred an elevated risk of MI and cardiovas-cular mortality (Nissen & Wolski, 2007).

At present, statins remain the drug of choice for the treatment andprevention of CVD, due to their beneficial effects on cardiovascularmortality. Nonetheless, it is clear that PPAR agonists, such as fibratesand glitazones confer some favourable cardiovascular effects, espe-cially in diabetic and/or obese individuals, and therefore holdtherapeutic potential for the treatment of CVD. However, significantfurther research is required in order to develop more specific drugswith reduced side effects which are able to compete with statins interms of clinical outcome.

2.6. Dual PPAR agonists

In light of the encouraging findings obtained from clinical trialsemploying PPAR agonists, recent attention has begun to focus oncompounds that are capable of targeting more than one PPAR isotype.Currently, these include PPARα/γ, PPARα/δ and PPARδ/γ dualagonists, together with PPARα/γ/δ pan agonists.

PPARα/γ dual agonists, such as tesaglitazar andmuraglitazar werecreated in order to elicit synergistic anti-diabetic and cardioprotectiveeffects (Chaput et al., 2000). Tesaglitazar has been demonstrated toreduce the development of atherosclerosis in an experimental mousemodel (Chira et al., 2007) and to improve atherogenic dyslipidaemiain non-diabetic patients with insulin resistance (Schuster et al., 2008).Furthermore, a newly developed PPARα/γ dual agonist has beenfound to not only improve insulin sensitivity, but also to prevent LVdysfunction in micewith combined leptin and LDL receptor deficiency(Verreth et al., 2006). Dual activation of both PPARα and PPARγ alsoappeared to reduce the side effects associated with PPARγ activationalone. In this situation, increases in body weight and adipogenesiscommonly encountered upon PPARγ treatment are counteracted byPPARα-induced decreases in food intake and fat deposition (Etgen etal., 2002; Carmona et al., 2005). Despite these promising observations,tesaglitazar and muraglitazar have been discontinued in Phase IIIclinical trials due to concerns relating to adverse effects on renalfunction (Conlon, 2006) and the incidence of cardiovascular events(Nissen et al., 2005), respectively. Current research in this area istargeted towards developing a more specific PPARα/γ agonist that isable to activate both receptors at therapeutic concentrations.

Novel PPARα/δ and PPARδ/γ dual agonists are currently underdevelopment and it is hoped that they will prove to be highly selectiveand beneficial in the treatment of CVD in both the absence or presenceof diabetes. Results with pan PPARα/γ/δ agonists have been moreencouraging, with bezafibrate, the only currently marketed panagonist, shown to improve insulin sensitivity, prevent myocardialischaemic injury and slow the development of coronary artery disease.Other pan agonists have also been demonstrated to have beneficialcardiovascular effects and are currently the subject of Phase I and IIclinical trials (Balakumar et al., 2007).

3. Conclusions

Since the discovery of nuclear PPARs in the early 1990s, thesubsequent development of PPAR agonists and gene-modified animalshas highlighted the involvement of these receptors in numerousbiological pathways. PPARs are known to play an important role in thecardiovascular system and have been implicated in several CVDs.However, the complexity of PPAR activation, in combinationwith theirdiverse tissue distribution and lack of specificity of currently availablePPAR agonists makes therapeutic modification of PPAR pathways achallenging goal. Further research aimed at the development of moreeffective agonists, together with pan agonists and SPPARM com-pounds will address some of the issues currently surrounding thepotential use of PPAR activators in the treatment of CVD. However, adetailed understanding of the role of PPARs in the cardiovascularsystem is required in order to delineate the precise mechanisms bywhich PPARs may modify cellular CVD processes and enableidentification of effective therapeutic targets.

Acknowledgment

The author's work is supported by the Medical Research Council.

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Significance of peroxisome proliferator-activated receptors in the cardiovascular system in health...

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