Current Molecular Pharmacology, 2012, 5, 241-247 241

This review is part of a Special Issue on PPAR Ligands and Cardiovascular Disorders: Friend or Foe. This Special Issue carries the following articles: Editorial: PPAR Ligands and Cardiovascular Disorders: Friend or Foe • The involvement of PPARs in the causes, consequences and mechanisms for correction of cardiac lipotoxicity and oxidative stress. • Healing the diabetic heart: modulation of cardiometabolic syndrome through peroxisome proliferator activator receptors (PPARs). • Effects of PPARγ agonists against vascular and renal dysfunction. • Use of clinically available PPAR agonists for heart failure; do the risks outweigh the potential benefits? • Assessment of cardiac safety for PPARγ agonists in rodent models of heart failure: A translational medicine perspective. • Peroxisome proliferator-activated receptorγ (PPARγ) agonists on glycemic control, lipid profile and cardiovascular risk. • Effects of PPARγ ligands on vascular tone. • PPARγ agonists in polycystic kidney disease with frequent development of cardiovascular disorders. Pitchai Balakumar and Gowraganahalli Jagadeesh Guest Editors Healing the Diabetic Heart: Modulation of Cardiometabolic Syndrome through Peroxisome Proliferator Activated Receptors (PPARs)

Tom Hsun-Wei Huang* and Basil D. Roufogalis

Faculty of Pharmacy, University of Sydney, NSW 2006, Australia Abstract: Cardiometabolic syndrome is a mixture of interrelated risk factors predisposing individuals to elevated risk of atherosclerotic cardiovascular disease and type 2 diabetes mellitus. Nuclear receptors, specifically peroxisome proliferator-activated receptors (PPARs), were identified to play a pivotal role in the regulation of metabolic homeostasis. However, with currently under intense scrutiny great concerns have arisen regarding the safety of the PPAR-γ agonist family as a whole. This review discusses the current concern with PPAR-γ agonists by exploring if PPARs can still be considered worth pursuing as a viable target for cardiovascular diseases. We examine current research focusing on identifying ligands that are dual and pan-PPAR agonists, selective PPAR-γ modulators, PPAR-β/δ agonists and that are of natural origin. Keywords: Cardiometabolic syndrome, diabetes mellitus, herbal and traditional natural medicines, peroxisome proliferator- activated receptor-γ.

CARDIOMETABOLIC SYNDROME: AN INTRO- risk factors such as increasing age, being female, sedentary DUCTION lifestyle and diabetes mellitus in parents, further hasten the development of cardiometabolic syndrome [5-7]. A meta- Cardiometabolic syndrome, also known as “Metabolic analysis has shown a relative risk of 2.2- and 1.9- fold for Syndrome” or “Syndrome X”, comprises a mixture of cardiovascular events and death, respectively, in almost all interrelated risk factors of metabolic origin predisposing 175,000 patients with cardiometabolic syndrome [8]. individuals to elevated risk of atherosclerotic cardiovascular Therefore, the underlying mechanisms leading to this disease and type 2 diabetes mellitus [1, 2]. Insulin resistance clustering of features appears more complicated than merely is considered to underlie this risk-factor cocktail and has the presence of insulin resistance or hyperinsulinemia, but been identified as a major contributor to the development of rather suggests a marriage of both pro-thrombotic and pro- metabolic syndrome [3]. Clinical risk factors include inflammatory states [9]. atherogenic dyslipidemia associated with low levels of high- Modern clinicians are confronted not only with the density lipoprotein cholesterol (HDL-C) and high levels of microvascular complications related to hyperglycemia but triglyceride (TG) and elevated blood pressure and plasma also with atherosclerotic macrovascular consequences of the glucose levels (Table 1). Low HDL-C levels are associated with adverse cardiologic outcomes, and have been found in metabolic syndrome [10]. The adoption of healthy behavior is the most fundamental therapeutic strategy for the most studies of intermittent claudication, there being a strong individual at increased cardiometabolic risk [9]. Clinical trial inverse relationship between HDL-C levels and claudication evidence shows that weight loss and increased physical severity [2]. Amelioration of these risk factors is considered activity are very effective in reversing cardiometabolic risk key to reducing mortality associated with obesity co- [11]. However, these health behavior modifications are often morbidities. Cardiometabolic syndrome is also characterized by hyperinsulinemia, low glucose tolerance and truncal difficult to maintain long-term. Thus, medicinal therapy or surgery intervention may be required to reinforce health obesity [4]. Recent studies have confirmed that independent behavior and to reduce cardiometabolic risk. In the last

decade, much attention has been focused on several

*Address correspondence to this author at the Faculty of Pharmacy, molecular drug targets with the potential to prevent or treat University of Sydney, NSW 2006 Australia; Tel: +61 2 9351 3234; Fax: 61 metabolic disorders, and in particular, nuclear receptors have 2 9351 4391; E-mail: [email protected] attracted much attention due to their regulatory roles in both

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Table 1. Clinical definitions of cardiometabolic syndrome [1,2]).

World Health Organization (WHO) National Cholesterol Education Program International Diabetes Federation (IDF) (NCEP)

Insulin resistance and/or impaired fasting glucose 3 of 5 are present Central obesity (waist circumference ≥ 90 cm plus at least two of the following: men and ≥ 80 cm women) plus at least two of the following: Obesity: BMI > 30 and/or Waist-to-hip ratio > 0.9 Obesity: Waist > 102 cm men and 88 cm women HDL-C: <40 mg/dL men and <50 mg/dL men and 0.95 women HDL-C: <40 mg/dL men and <50 mg/dL women women or specific treatment Dyslipidemia: HDL-C < 35 mg/dL men and < 40 Triglycerides: ≥ 150 mg/dL Triglycerides: ≥ 150 mg/dL specific treatment mg/dL women and/or triglycerides > 10 mg/dL Hypertension: >130/85 mmHg and/or Hypertension: >130/85 mmHg and/or Hypertension: >140/90 mmHg and/or anti-hypertensive medications treatment for hypertension anti-hypertensive medications Fasting plasma glucose: ≥ 100 mg/dL Fasting plasma glucose: ≥ 100 mg/dL Microalbuminuria: Albumin/creatinine ratio 25-250 glucose homeostasis and lipogenesis [12, 13]. Nuclear Recruitment of PPAR co-factors to assist the gene receptors are a family of zinc-containing proteins that transcription processes is carried out by the ligand-dependent interact with steroids, hydrophobic hormone molecules or activation function 2 (AF-2), which is located in the E/F xenobiotics [14]. Of those, peroxisome proliferator-activated domain [22]. receptors (PPARs) were identified to play a pivotal role in the regulation of metabolic homeostasis [15]. This review THE PROBLEM WITH CURRENT PPAR-γ LIG- aims to discuss the current concern with PPAR-γ-targeting ANDS (ROSIGLITAZONE) drugs (specifically the marketed agonists) and explore if PPARs may still provide a viable target worth pursuing Only a handful of available pharmaceutical agents are despite the concern. capable of adequately addressing the multi-factorial abnormalities attributed to cadiometabolic syndrome. As diminished insulin sensitivity in target tissues has been PEROXISOME PROLIFERATOR-ACTIVATED RE- considered to play an important role in pathogenesis of the CEPTORS (PPARs) cardiometabolic syndrome, insulin-sensitizing drugs, such as The PPARs belong to a subfamily of the nuclear receptor the thiazolidinedione PPAR-γ agonists, have been widely used [23]. Currently, two available , superfamily and are ligand-activated transcription factors, (Actos®, Takeda Pharmaceuticals, Deerfield, which heterodimerize with the retinoic X receptor (RXR) IL) and rosiglitazone (AvandiaTM, GlaxoSmithKline, and PPAR response elements (PPRE) localized in the Research Triangle Park, NC), have limited efficacy and promoter region of target genes (Fig. 1a) [16]. The ligand tolerability, accompanied by side effects such as bone binding domain (LBD) facilitates the heterodimerization of PPARs with the co-receptor RXR and docking to promoter fracture, weight gain, fluid retention, edema, and congestive heart failure [24-30]. Thus, it is apparent that a safer insulin regions of genes, which regulate transcription in a ligand- sensitizer is needed. In early 2010, the United States Food dependent manner through the differential recruitment of co- and Drug Administration (FDA) advisory panel delivered a activators and co-repressors [13, 17, 18]. To date, three mixed verdict regarding rosiglitazone’s future, as potential PPAR isoforms have been identified, PPAR-α (NR1C1), cardiovascular risks have raised substantial concern in the PPAR-β/δ (NR1C2) and PPAR-γ (NR1C3), with each having similar protein structure despite differences in coding past 3 years [31]. The FDA’s final decision was to recommend warnings and/or restrictions on its usage, with genes [19]. PPAR-α is associated with lipid metabolism and additional emphasis regarding the increase in congestive is the target of , whereas PPAR-γ is associated with heart failure and myocardial infarction associated with glucose homeostasis and is the site of thiazolidinediones rosiglitazone specifically, rather than a thiazolidinedione docking (Table 2) [20]. PPAR-β/δ has been associated with class effect as a whole [32]. A recent meta-analysis and modulation of immune response and energy homeostasis and has been subject to much research in recent years (Table 2), clinical trial have shown that pioglitazone, a drug in the same class, is associated with a reduced risk of although there are no approved therapeutic indications [18]. cardiovascular disease and significantly reduced the All three PPAR isoforms possess similar structural and principal endpoints of time to death, myocardial infarction functional features (Fig. 1b). Principally, four functional and stroke [33, 34]. Interestingly, a recent trial combining domains have been identified, called A/B, C, D and E/F. The pioglitazone with alogliptin (a noncovalent, selective N-terminal of A/B domain contains a ligand-independent activation function 1 (AF-1) responsible for the inhibitor of dipeptidyl peptidase-4) has shown reversal of the multiple metabolic defects in type 2 diabetes mellitus, phosphorylation of PPAR [21]. The DNA binding domain or possibly through pioglitazone exerting a positive effect on C domain promotes the binding of PPAR to the PPRE in the direct PPAR- modulation of insulin secretion and promoter region of target genes [17]. The D site is a docking γ lipotoxicity, while alogliptin improves islet function by domain for cofactors. The E domain or LBD is responsible increasing insulin secretion and lowering glucagon secretion for ligand specificity and activation of PPAR binding to the PPRE, which increases the expression of targeted genes [22]. in response to elevated plasma glucose levels [35]. Such

Modulation of Cardiometabolic Syndrome through PPARs Current Molecular Pharmacology, 2012, Vol. 5, No. 2 243

9-cis RA Retinoic X Ligands PPAR- Receptor (a) Nucleus

PPAR PPRE

Cytoplasm

DNA Activation Activation sequence Hinge Heterodimerization Function-1 recognition region Function-2 (b) AF-1 AF-2

A/B C DEF Fig. (1). a-b. PPAR activators (natural and synthetic) and related PPAR-isotypes [13].

Table 2. Synthetic and natural ligands modulating PPARs activities relating to cardiometabolic functions [13].

PPAR Synthetic Ligands Natural Ligands Major Cardiometabolic Functions

PPAR-α Hypolipidemic drugs (, Saturated & unsaturated fatty acids Lipid metabolism genfibrozil Plasticizers, ureidofibrates) -derived eicosanoids from Inflammation control WY14643, JTT-501, the lipoxygenase pathway (8-S- Vascular function & integrity GW-2331 & PD72953 hydroxyeicosatetraenoic acid & )

Insulin Oxidized LDL PPAR-δ/β Leukotriene antagonist (L-165041) Saturated and unsaturated fatty acids Lipid metabolism Phenylacetic derivatives (L-796449 & L- Eicosanoids: PGA1 & PGD2 Glucose homeostasis 783483, Vascular function & integrity GW-2433, GW-501516, GW0742X Carbaprostacyclin PPAR-γ Thiazolidinediones: (pioglitazone, Linoleic acid, linolenic acid, arachidonic Insulin sensitivity , rosiglitazone, MCC-555) acid, eicosapentenoic acid, 15-deoxy Δ12, Glucose homeostasis 14-prostaglandin J2 Isoxazolidinedione (JTT-501) Inflammation control 15-LOX metabolites (9-HODE & 13- Tyrosine-based agonist (GI2-62570, GW- Vascular function & integrity 1929, & GW-7845) HODE)

α-alcoxy-β- phenylpropanoic acid) LTD4 receptor antagonist (LY-171883) COX inhibitors (indomethacin, , fenoprofen, & flufenamic acid) Docosohexanoic derivatives combination is shown to be well tolerated and to feature of new drugs for managing the metabolic syndrome. significantly lower HbA1c, with reduced risk of hypoglycemia The general design of PPAR agonists comprises an acidic [35]. group attached to an aromatic part, which in turn is linked to the aromatic tail through a spacer [36]. The latter authors IS THERE A FUTURE FOR PPAR LIGANDS IN have shown that by using indole and tetrahydroquinoline TREATING CARDIOMETABOLIC SYNDROME? rings as aromatic head groups and linking them to 4- phenylbenzophenone and other tail groups through spacers With increased evidence that obesity is a major driver of identifies potential PPAR agonists with varying levels of cardiometabolic risk, beneficial effects on body weight activity and selectivity toward α, β/δ and γ subtypes Table 1. decrease or avoidance of further weight gain is an attractive Since the approval of thiazolidinediones, more than 50 new 244 Current Molecular Pharmacology, 2012, Vol. 5, No. 2 Huang and Roufogalis investigational ligand applications have been registered for efficacy [20]. However, studies have shown that selective PPARs, although none has yet reached the market due to modulation, as opposed to simple partial agonism, could potential safety concerns [37]. invoke different patterns of activity [49, 50]. Interestingly, all marketed PPAR-α agonists belong to A selective modulator is distinct from a partial agonist in the fibrate class (fenofibrate and ) and they are that dose–response relations for various activities are widely prescribed as hypolipidemic agents to reduce uncoupled from each other [51]. This specificity may result triglycerides, increasing plasma HDL-C [38]. They also from a right-shift in dose-response curve, such that the reduce vascular inflammation and thrombogenicity [39], ligand is a more potent inducer of some activities or provides hence reducing the progression of atherosclerosis and a difference in the maximal response, such that it is more minimizing the incidence of coronary heart disease [40]. efficacious in inducing some activities compared to others. This selective modulator could potentially be a more potent Dual and Pan-PPAR Agonists inducer of insulin sensitization, with lower maximal activity for effects on adipose generation, loss of bone mineral In recent years, identifying drugs acting on different density, fluid retention and congestive heart failure [30, 49]. PPAR isotypes has been advocated for broader therapeutic Therefore, research in recent years has focused on the potential for patients suffering from cardiometabolic development of selective PPAR-γ modulators. These are syndrome. Non-specific PPAR agonists (dual agonists and PPAR-γ ligands with insulin-sensitizing activity and lower pan-PPAR agonists) have been constructed to obtain stimulation of adipogenesis. This is achieved by binding to synergism on lipid and glucose homeostasis from the ligand-binding pocket of the PPAR-γ receptor in distinct simultaneous activations of PPAR-α, PPAR-β/δ and/or manners, inducing the displacement of the differential PPAR-γ [13, 41, 42]. was the first non- cofactor and specific gene expression in a tissue specific thiazolidinedione/fibrate PPAR-α/γ dual agonist identified. manner [20]. Halofenate (MK-102 or metaglidasen However, phase III clinical trials have found an increased (Metabolex Inc, Hayward, CA), a selective PPAR-γ incidence of cardiovascular adverse events with this modulator, has been shown to selectively regulate the compound [43]. Similarly, other PPAR-α/γ dual agonists expression of multiple PPAR-γ responsive genes in 3T3-L1 such as ragaglitazar, , farglitazar, TAK559 and adipocytes, and to demonstrate acute anti-diabetic properties KRP297 also followed similar fates, and were discontinued in diabetic ob/ob mice [20, 52- 54]. due to adverse safety profiles compared to selective agonists [12, 41]. As for pan-PPAR agonists (activators of all three Interestingly, an isoquinoline derivative PA-082 PPAR subtypes), the question of effectiveness and safety of (Hoffmann-La Roche AG, Basel, Switzerland) has been this sub-family of ligands in modulating cardiometabolic shown to preferentially recruit PPAR-γ-coactivator-1α to the disorders is yet to be answered. Studies with (the receptor compared to rosiglitazone, inducing glucose uptake first clinically tested PPAR pan agonist) have shown it to and insulin signaling in mature adipocytes [55]. INT131 (T- raise HDL-C, reduce triglycerides, improve insulin 131 or AMG131, InteKrin Therapeutics Inc, Los Altos, CA) sensitivity, and reduce blood glucose levels [44]. Currently, is a sulfonamide found to interact with the PPAR-γ binding CS-204, DRF-11605, GW-625019, GW-677954, LY-465608 pocket in an overlapping region but in a manner different and PLX-204 are under investigation as potentially lead from that of rosiglitazone [56]. In vivo studies have shown therapeutic agents for the treatment of cardiometabolic that INT131 demonstrates similar or better efficacy and syndrome [45, 46]. potency compared to rosiglitazone. Additionally, it lacks the fluid retention and cardiac hypertrophy observed with rosiglitazone [47]. In recent years, , an anti- Selective PPAR-γ Modulators herpertensive agent was found to be a selective partial PPAR-γ is capable of regulating a large array of PPAR-γ modulator, where traditionally it was marketed as an responses due to the vast number of possible ligand-binding angiotensin II receptor antagonist [57, 58]. Studies have conformations and responsive genes [47]. The shown that telmisartan reduces glucose, insulin, and conformational state of PPAR-γ is crucial for the activity it triglyceride levels in rats fed a high fat, high carbohydrate elicits, since the conformation of PPAR-γ determines the diet [57, 59] and is associated with a markedly reduced affinity of co-repressors and co-activators [20, 48]. Different incidence of new-onset diabetes in different patient ligands bind to the PPAR-γ ligand binding domain in populations in large clinical trials [60]. Hence, telmisartan is different ways and induce different bound conformations and being coined a “cardiometabolic sartan” that targets both interactions with co-regulators, thus inducing different diabetes and cardiovascular disorders in hypertensive transcription patterns. For example, the activation by a patients [61]. Interestingly, telmisartan treatment was shown partial PPAR-γ agonist (GW0072) will elicit the same to decrease weight of visceral adipose tissue and increase activation pattern but has a lower maximal activity compared serum adiponectin level in diet-induced obese mice [62]. In with a full agonist (e.g., rosiglitazone) [47]. Furthermore, the combination with amlodipine, a calcium channel blocker, it tight hydrogen bonding of rosiglitazone to the activation was shown to exert favorable cardiometabolic actions in function helix AF-2, results in a strong recruitment of co- elderly hypertensive patients [63]. regulators and high maximal activity, whereas GW0072 fits into the same binding pocket but does not contact AF-2 and PPAR-β/δ induces a conformation intermediate between the unbound PPAR-γ and fully bound PPAR-γ effect [20]. This results in PPAR-β/δ is ubiquitously expressed and is responsible a weaker recruitment of co-regulators and a low maximal for diverse processes ranging from the regulation of energy Modulation of Cardiometabolic Syndrome through PPARs Current Molecular Pharmacology, 2012, Vol. 5, No. 2 245 homeostasis and thermogenesis, to keratinocyte proliferation therapy may need to be co-prescribed fish oil to lower the and differentiation during wound healing and stimulation of risk of rosiglitazone-mediated cardiac dysfunction. the β-oxidation of fatty acids and reversal of cholesterol transport [18]. Because of such diverse modulatory CONCLUSIONS properties, it has been proposed that PPAR-β/δ ligands are potential candidates to treat cardiometabolic syndrome [64]. Cardiometabolic disorders are a collection of modifiable Studies with the potent PPAR-β/δ agonist, GW501516, have risk factors predisposing individuals to cardiovascular and shown it to prevent the development of hypertriglyceridemia metabolic disease morbidity. It is crucial for new ligands to caused by a high-fat diet and inhibit the reduction in hepatic be identified that may one day manage the multiple phospho-AMP-activated protein kinase levels induced by complications resulting from these disorders. The prevalence such a diet. It also increases hepatic fatty acid oxidation by of cardiometabolic syndrome is increasing. PPARs are an enhancing the activity of the lipin 1-PPAR-α-PPAR-γ attractive and still relatively unexploited target for drug coactivator 1α pathway [65, 66]. The clinical significance of development due to their regulatory roles in both glucose PPAR-β/δ agonists still needs to be validated with robust homeostasis and lipogenesis. Ligands targeting different clinical trials, however it is possible that PPAR-β/δ might be PPAR isotypes are being actively examined to hopefully one the key PPAR isoform in reversing cardiometabolic day provide the broader therapeutic potential in modulating syndrome. both glucose and lipid metabolism for patients suffering from cardiometabolic syndrome. Further exploration of the Natural Modulators diverse pharmacophores of PPARs will allow design of more novel compounds capable of binding the receptor but Natural products are a rich source of ligands for nuclear minimizing potential side effects. PPAR ligands are unique receptors and are promising therapeutic agents in clinical and may differentially modulate PPAR activity and the practice. In particular, plants provide an abundant source of downstream related genes. Therefore, despite the failures of biologically active molecules that have played critical roles earlier marketed PPAR agonists (specifically PPAR-γ in pharmacology [67]. In a previous review by Huang et al. agonists), the potential for new compounds to target the (2009), the authors summarized extensive current research PPAR family, with a safer pharmacological profile against being conducted in identifying herbal derived nuclear atherosclerotic cardiovascular disease and type 2 diabetes receptor modulators. In this paper, the focus will be on the mellitus should not be discarded. recent natural ligands identified as suitable candidates for treatment of cardiometabolic syndrome [13]. ACKNOWLEDGEMENTS Through pharmacophore-based virtual screening, oleanonic acid was identified from the oleoresin of Pistacia We thank the National Institute of Complementary lentiscus var. Chia (Chios mastic gum) as a potential PPAR-γ Medicine (NICM) for support of this project. modulator [48], as competition assays demonstrated that oleanonic acid was able to dose dependently antagonize ABBREVIATIONS rosiglitazone mediated PPAR-γ transcriptional activation [48]. Polyphenols (catechins) found in green tea (Camellia PPARs = peroxisome proliferator-activated receptors sinensis, Theaceace) are found to treat the symptoms associated with cardiometabolic syndrome [68] and in vivo PPRE = PPAR response elements studies have shown them to favorably regulate the genes RXR = retinoic X receptor relevant to insulin resistance, PPAR-γ, lipoprotein lipase and glucose transporter 4 (GLUT4) [69]. Recently, a Chinese LBD = ligand binding domain herbal extract (SK506) containing active ingredients from G. AF-2 = activation function 2 pentaphyllum, C. chinensis and S. mitiorrhiza was shown to improve glucose intolerance and enhance glycogen synthesis GLUT4 = glucose transporter 4 in adipose tissue during hyperinsulinemic-euglycemic clamp in vivo [70]. , a compound found in SK506 is REFERENCES known to stimulate AMP-activated protein kinase activity, leading to increased GLUT4 expression and translocation [1] Dervaux, N.; Wubuli, M.; Megnien, J.L.; Chironi, G..; Simon, A. Comparative associations of adiposity measures with [71]. Interestingly, whereas rosiglitazone treatment is cardiometabolic risk burden in asymptomatic subjects. considered to increase the incidence of heart failure in Atherosclerosis, 2008, 201, 413-417. diabetic patients, in an in vivo model it was shown that when [2] Vykoukal, D.; Davies, M.G.. Vascular biology of metabolic co-administered with fish oil the combination suppressed syndrome. J. Vasc. 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Received: May 12, 2011 Revised: June 13, 2011 Accepted: September 19, 2011

PMID: 22122453