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Modulation of Cardiometabolic Syndrome Through Peroxisome Proliferator Activator Receptors (Ppars)

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Modulation of Cardiometabolic Syndrome Through Peroxisome Proliferator Activator Receptors (Ppars) 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 rosiglitazone currently under intense scrutiny great concerns have arisen regarding the safety of the thiazolidinedione 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 1874-4702/12 $58.00+.00 © 2012 Bentham Science Publishers 242 Current Molecular Pharmacology, 2012, Vol. 5, No. 2 Huang and Roufogalis 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 thiazolidinediones, superfamily and are ligand-activated transcription factors, pioglitazone (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 fibrates, whereas PPAR-γ is associated with heart failure and myocardial infarction associated with glucose homeostasis and is the site of thiazolidinediones rosiglitazone specifically,
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