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Cardiovascular Research 2005 65(4):772-781; doi:10.1016/j.cardiores.2004.12.008
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Copyright © 2004, European Society of Cardiology

Beneficial effects of PPAR-{gamma} ligands in ischemia–reperfusion injury, inflammation and shock

Maha Abdelrahman, Ahila Sivarajah and Christoph Thiemermann*

Centre for Experimental Medicine, Nephrology and Critical Care, William Harvey Research Institute, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Charterhouse Square, London, EC1M 6BQ, UK

* Corresponding author. Tel.: +44 207 882 6118; fax: +44 207 251 1685. Email address: c.thiemermann{at}qmul.ac.uk

Received 7 October 2004; revised 22 November 2004; accepted 2 December 2004


   Abstract
Top
 Abstract
1. Introduction
 2. Endogenous PPAR-{gamma}...
 3. Synthetic PPAR-{gamma}...
 4. PPAR-{gamma} in inflammation
 5. Myocardial...
 6. Ischemia/reperfusion injury...
 7. Shock models
 8. Concluding remarks
 References
 
Peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. PPAR-{gamma} regulates gene expression by forming a heterodimer with the retinoid X receptor (RXR) before binding to sequence-specific PPAR response elements (PPREs) in the promoter region of target genes, thereby regulating several metabolic pathways, including lipid biosynthesis and glucose metabolism. Thiazolidinediones (TZDs, i.e. rosiglitazone, pioglitazone), which are synthetic PPAR-{gamma} agonists, act as insulin sensitizers and are used in the treatment of type 2 diabetes. In the last few years, it has, however, become evident that the therapeutic effects of PPAR-{gamma} ligands reach far beyond their use as insulin sensitizers. Recently, PPAR-{gamma} has been implicated as a regulator of cellular inflammatory and ischemic responses. PPAR-{gamma} agonists may exert their anti-inflammatory effects by negatively regulating the expression of pro-inflammatory genes induced during macrophage differentiation and activation, by either PPAR-{gamma}-dependent or -independent mechanisms. Several lines of evidence suggest that TZDs protect the heart and other organs against the tissue injury caused by ischemia/reperfusion (I/R) injury and shock. This review discusses the anti-inflammatory signalling pathways activated by PPAR-{gamma}, as well as the potential therapeutic effects of PPAR-{gamma} agonists in animal models of ischemia/reperfusion, inflammation and shock.

KEYWORDS PPAR-{gamma}; Regional myocardial infarction; Inflammation; Ischemia; Reperfusion; Shock


   1. Introduction
Top
 Abstract
 1. Introduction
2. Endogenous PPAR-{gamma}...
 3. Synthetic PPAR-{gamma}...
 4. PPAR-{gamma} in inflammation
 5. Myocardial...
 6. Ischemia/reperfusion injury...
 7. Shock models
 8. Concluding remarks
 References
 
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily related to retinoid, steroid, and thyroid hormone receptors [1]. All members of this superfamily have a similar structural organisation: an amino-terminal region that allows ligand-independent activation, followed by a DNA-binding domain (two zinc fingers) and, at the carboxyl-terminal, a ligand-dependent activation domain [2]. To date, three subtypes of PPAR have been identified PPAR-{alpha}, PPAR-{gamma}, and PPAR-β (also called -{delta}). The three isoforms are the products of distinct genes: the human PPAR-{alpha} gene was mapped on chromosome 22 in the general region 22q12–q13.1, the PPAR-{gamma} gene is located on chromosome 3 at position 3p25, whereas PPAR-β has been assigned to chromosome 6, at position 6p21.1–p21.2 [3–5]. The name PPAR is derived from the fact that activation of PPAR-{alpha}, the first member of the PPAR family to be cloned, results in peroxisome proliferation in rodent hepatocytes [6]. Activation of neither PPAR-β nor PPAR-{gamma}, however, elicits this response.

The tissue distribution varies greatly between the subtypes. PPAR-{alpha} is found mainly in the liver, kidney, skeletal, and cardiac muscle, PPAR-β is ubiquitously expressed, whereas PPAR-{gamma} is mainly found in adipocytes and in cells of the immune system such as monocytes/macrophages, B and T cells, and dendritic cells [7–14]. There are two isoforms of PPAR-{gamma}, PPAR-{gamma}1 and PPAR-{gamma}2. Differential promoter usage and alternate splicing of the gene generates three mRNA isoforms. PPAR-{gamma}1 and PPAR-{gamma}3 mRNA both encode the PPAR-{gamma}1 protein product which is expressed in most tissues, whereas PPAR-{gamma}2 mRNA encodes the PPAR-{gamma}2 protein, which contains an additional 28 amino acids at the amino terminus and is specific to adipocytes [15].

1.1. Mechanisms of transcriptional transactivation
PPAR-{gamma} regulates gene expression by binding as a heterodimer with the retinoid X receptor (RXR)–a member of the nuclear hormone receptor superfamily activated by binding of 9-cis-retinoic acid. The RXR family comprises three different gene isoforms: RXR{alpha}, RXRβ, and RXR{gamma}. The human RXR{alpha} gene is located on 9q34.3 and encodes two major isoforms: RXR{alpha}1 and RXR{alpha}2. The RXRβ is localised on chromosome 6p21.3, with two main isoforms: RXRβ1 and RXRβ2. RXR{gamma} is located on 1q22–23, and has two isoforms, RXR{gamma}1 and RXR{gamma}2. RXR is widely expressed in several tissues and cells including adipose tissue, liver, kidneys, small intestine, cardiac myocytes, and monocytes/macrophages [16].

The PPAR-{gamma}/RXR heterodimer then binds to sequence-specific PPAR response elements (PPREs) in the promoter region of target genes, thereby acting as a transcriptional regulator (Fig. 1). In the absence of a ligand, to prevent PPAR-{gamma}/RXR binding to DNA, high-affinity complexes are formed between the inactive PPAR-{gamma}/RXR heterodimers and co-repressor molecules, such as nuclear receptor co-repressor or silencing mediator for retinoic receptors. On ligand binding and activation, these co-repressors are displaced and the heterodimer is free to bind to the response element in the promoter region of the relevant target genes, resulting in either activation or suppression of a specific gene. Recruitment of co-activator proteins is required for transcriptional interaction of PPAR-{gamma} with motifs in the PPRE. A thorough review of the mechanism of transcriptional transactivation of PPAR-{gamma} can be found in the literature [6].


Figure 1
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  		Fig. 1 Activation of PPAR-{gamma}. Following ligand binding, heterodimerisation of peroxisome proliferator-activated receptor {gamma} (PPAR-{gamma}) with the retinoid X receptor (RXR) produces an active transcription complex that associates with transcriptional co-activators and binds to sequence specific PPAR response elements (PPREs) located in target genes.

 
1.2. Mechanisms of transcriptional transrepression
Apart from its role during transcriptional regulation, which requires DNA-binding, PPAR-{gamma} can also function in a DNA-binding-independent manner to transrepress different target genes. Several lines of evidence suggest that PPAR-{gamma} may exert anti-inflammatory effects by negatively regulating the expression of pro-inflammatory genes induced during macrophage differentiation and activation (see Fig. 2). To date, several potential mechanisms for PPAR-{gamma}-agonist-dependent transcriptional transrepression of the pro-inflammatory macrophage response have been suggested. First, competition for limited amounts of essential, shared transcriptional co-activators may play a role in transrepression. In vitro studies have revealed a ligand type-specific direct interaction of PPAR-{gamma} with several transcriptional co-activators, such as SRC-1, TIF2, AIB-1, CBP, p300, TRAP220, and DRIP205 [17]. The activated PPAR-{gamma}/RXR heterodimer reduces the availability of co-activators required for gene induction by other transcriptional factors. Thus, without distinct cofactors, transcriptional factors, such as activated protein-1 (AP-1), nuclear factor-{kappa}B (NF-{kappa}B), nuclear factor of activated T cells (NFAT) or signal transducer and activator of transcription (STAT), cannot cause gene expression. In lipopolysaccharide (LPS)/ interferon-{gamma} (IFN-{gamma}) stimulated macrophages, attenuation of inducible nitric oxide synthase (iNOS) expression in response to PPAR-{gamma} activation has been explained by targeting of the two general co-activators CREB-binding protein (CBP) and p300 by PPAR-{gamma} [18].


Figure 2
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  		Fig. 2 The tissue injury associated with for example ischemia–reperfusion injury of the heart results in the activation of a number of transcription factors including nuclear factor-{kappa}B (NF-{kappa}B), activated protein-1 (AP-1), nuclear factor of activated T cells (NFAT), and signal transducer and activator of transcription (STAT). This results in the up-regulation of the genes for a number of primarily pro-inflammatory cytokines, chemokines, and adhesion molecules, all of which act in concert to orchestrate an inflammatory response. When this inflammatory response is excessive, this may further aggravate the tissue injury (initial insult). Tissue injury in the heart and other organs, however, also leads to an up-regulation of the expression of PPAR-{gamma}. We know today that activation of PPAR-{gamma} (by either endogenous or exogenous ligands) inhibits the activation of the transcription factors NF-{kappa}B, AP-1, NFAT, and STAT. This subsequently attenuates the formation of cytokines, chemokines, and adhesion molecules and, therefore, reduces excessive inflammation and tissue injury. Specifically ligands of PPAR-{gamma} have been shown to inhibit the expression of the following (a) cytokines: interleukin -1β (IL-1β), IL-2, IL-6, IL-10, IL-12, tumour necrosis factor-{alpha} (TNF-{alpha}), interferon-{gamma} (IFN-{gamma}); (b) chemokines: monocyte chemoattractant protein-1 (MCP-1); (c) adhesion molecules: intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), platelet/endothelial cell adhesion molecule-1 (PECAM-1), integrins (CD11b/CD18), L-selectin; (d) others: inducible nitric oxide synthase (iNOS), cycloxygenase-2 (COX-2), CD40/CD40 ligand (CD40L), matrix metalloproteinase-9 (MMP-9), CCAT/enhancer-binding proteins (C/EBPs).

 
Second, PPAR-{gamma}/RXR complexes may cause a functional inhibition by directly binding to transcription factors, preventing them from inducing gene transcription. This method of transrepression, mediated by physical interaction, has been reported for proteins of the NF-{kappa}B family, such as p50 and p65 [19]. In addition, NFAT precipitation experiments in T cells revealed a direct contact with PPAR-{gamma}, with NFAT sequestration accounting for suppression of T cell proliferation and activation [14].

Another mechanism, which may result in transrepression, involves regulation of the mitogen-activated protein kinase (MAPK) cascade. PPAR-{gamma}/RXR heterodimers may inhibit phosphorylation and activation of several members of the MAPK family. In a study carried out in PPAR-{gamma}+/– heterozygous mice, activation of c-Jun-N-terminal kinase (JNK) and p38 in response to 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis was significantly reduced compared with wild-type littermates [20].


   2. Endogenous PPAR-{gamma} ligands
Top
 Abstract
 1. Introduction
 2. Endogenous PPAR-{gamma}...
3. Synthetic PPAR-{gamma}...
 4. PPAR-{gamma} in inflammation
 5. Myocardial...
 6. Ischemia/reperfusion injury...
 7. Shock models
 8. Concluding remarks
 References
 
PPAR-{gamma} is bound and activated by a variety of lipophilic ligands, including long-chain polyunsaturated fatty acids and several eicosanoids. The essential fatty acids arachidonic acid, gamolenic acid, docosahexanoic acid, and eicosapentaenoic acid, as well as modified oxidised lipids [9- and 13-hydroxyoctadecadienoic acid (9- and -HODE) and 12- and 15-hydroxyeicosatetraenoic acid (12- and 15-HETE)], bind to and activate PPAR-{gamma} [21]. The naturally occurring PPAR-{gamma} agonist, which has most commonly been used experimentally, is 15-deoxy-{Delta}12,14-PGJ2 (15d-PGJ2) [22].

The cyclopentenone prostaglandin (PG) 15d-PGJ2 was first discovered in 1983, following incubation of PGD2 for extended periods of time in the presence of albumin [23]. It, however, received relatively little attention until 1995 when two independent groups simultaneously reported that it is capable of activating PPAR-{gamma} [22,24]. As the endogenous ligand for PPAR-{gamma} was unknown, these papers sparked considerable interest, and it was hypothesised that 15d-PGJ2 may fulfil the role as the endogenous PPAR-{gamma} ligand. Although it is clear that 15d-PGJ2 can stimulate PPAR-{gamma}, for this to be correct, 15d-PGJ2 would have to act at concentrations consistent with its physiological levels. However, in contrast to other prostaglandins, which are normally active at low nM concentrations, the concentrations of 15d-PGJ2 required to stimulate PPAR-{gamma} are generally reported to be in the µM range [25]. In addition, whilst in vitro albumin-catalysed dehydration of PGD2 yields PGJ2, which undergoes further dehydration resulting in the formation of 15d-PGJ2, there is no evidence for the enzymatic formation of these prostaglandins in vivo. Using a highly sensitive liquid chromatography/tandem mass spectrometry assay for 15d-PGJ2, Bell-Parikh and colleagues reported that although 15d-PGJ2 can be generated in vivo, the levels produced are not sufficient to be compatible with a role for this substance as an endogenous ligand for PPAR-{gamma} [26]. Thus, whether 15d-PGJ2 is the endogenous ligand for PPAR-{gamma} is still not clear. Nevertheless, 15d-PGJ2 is not only the most potent natural ligand for PPAR-{gamma} identified to date, but also by far the most commonly used naturally occurring PPAR-{gamma} agonist [22].

Due to the widespread use of 15d-PGJ2 as a pharmacological tool for defining the role of PPAR-{gamma}, it is important to note that 15d-PGJ2 can induce a variety of PPAR-{gamma}-independent responses, and 15d-PGJ2 has indeed been shown to induce responses in cells devoid of the receptor [27]. Many of these effects are mediated through covalent binding of 15d-PGJ2 to proteins; the reactive cyclopentenone ring of 15d-PGJ2 readily reacts with nucleophilic groups such as cysteinyl thiol groups of proteins. For example, in addition to inhibiting NF-{kappa}B activation via PPAR-{gamma}, 15d-PGJ2 has been reported to inhibit NF-{kappa}B-dependent transcription by two other distinct mechanisms. First, 15d-PGJ2 can interrupt NF-{kappa}B-dependent gene transcription by covalently binding to I{kappa}B kinase, preventing I{kappa}B degradation and nuclear entry of NF-{kappa}B [28,29]. The second mechanism by which 15d-PGJ2 interferes with NF-{kappa}B activation involves direct inhibition of binding of NF-{kappa}B to target DNA [29].


   3. Synthetic PPAR-{gamma} ligands
Top
 Abstract
 1. Introduction
 2. Endogenous PPAR-{gamma}...
 3. Synthetic PPAR-{gamma}...
4. PPAR-{gamma} in inflammation
 5. Myocardial...
 6. Ischemia/reperfusion injury...
 7. Shock models
 8. Concluding remarks
 References
 
In addition to natural ligands, a wide range of synthetic PPAR-{gamma} agonists have been developed. The most widely used belong to the thiazolidinedione (TZD) or glitazone class of anti-diabetic drugs used in the treatment of type 2 diabetes. These include rosiglitazone, pioglitazone, ciglitazone, and troglitazone. In January 1997, troglitazone was the first TZD to be approved as a glucose-lowering therapy for the treatment of patients with type 2 diabetes. Troglitazone was however withdrawn from the market in March 2000 following the emergence of a serious hepatotoxicity in some patients. The two currently available PPAR-{gamma} agonists, rosiglitazone and pioglitazone, were approved in the United States in 1999 and are currently used alone or in combination with other oral anti-diabetic agents for type 2 diabetes patients.

TZDs exert their insulin-sensitising and hypoglycaemic effects through stimulation of PPAR-{gamma} [30]. TZD-induced stimulation of PPAR-{gamma} results in an alteration in the transcription of several genes involved in glucose and lipid utilisation and energy balance such as GLUT4 glucose transporter and fatty acid transporter protein [31]. The involvement of PPAR-{gamma} in the pharmacological effects of TZDs has been supported by studies showing that their binding affinity to PPAR-{gamma} closely parallels their in vivo hypoglycaemic potency [21]. For instance, treatment of non-diabetic subjects or those with type 2 diabetes for three to six months with troglitazone, rosiglitazone, or pioglitazone increases insulin-stimulated glucose uptake in peripheral tissues, increases the ability of insulin to suppress endogenous glucose production and enhances insulin sensitivity in adipose tissue (measured from the ability of insulin to suppress free fatty acid concentrations) [32–35]. In addition, insulin secretory responses, even after adjustment for an improvement in insulin sensitivity, have increased in subjects with type 2 diabetes [36]. The pharmacology and clinical efficacy in humans goes beyond the topic of this review and the interested reader is referred to an excellent review of this topic [37].

In the last few years, there are numerous reports indicating that the therapeutic benefits of PPAR-{gamma} agonists may go far beyond their use in diabetes. In the following paragraphs, we will review and discuss the role PPAR-{gamma} in the pathophysiology of ischemia/reperfusion (I/R) injury, inflammation and shock, and particularly highlight the effects of endogenous or synthetic PPAR-{gamma} ligands in these disorders.


   4. PPAR-{gamma} in inflammation
Top
 Abstract
 1. Introduction
 2. Endogenous PPAR-{gamma}...
 3. Synthetic PPAR-{gamma}...
 4. PPAR-{gamma} in inflammation
5. Myocardial...
 6. Ischemia/reperfusion injury...
 7. Shock models
 8. Concluding remarks
 References
 
Inflammation, which plays an important role in many disease states, is associated with oxidative stress and enhanced expression of adhesion molecules in the vasculature, resulting in the infiltration of neutrophils and monocytes/macrophages. The release of pro-inflammatory cytokines and oxygen free radicals from the activated leukocytes can then in turn cause tissue damage. Several lines of evidence suggest that PPAR-{gamma} exerts anti-inflammatory effects by negatively regulating the expression of pro-inflammatory genes induced in response to macrophage differentiation and activation [38].

PPAR-{gamma} is expressed in human and murine monocytes/macrophages [3,39] and there is a link between the state of monocyte/macrophage differentiation or activation and PPAR-{gamma} expression. In the mouse, PPAR-{gamma} is expressed at low levels in non-activated macrophages, whereas much higher levels are expressed in activated peritoneal macrophages [39]. In human peripheral blood monocytes, a similar relationship between the state of differentiation and activation and PPAR-{gamma} expression has been described [8]. Activation of monocytes/macrophages with phorbol esters, oxidised LDL, macrophage colony-stimulating factor (MCSF), and granulocyte-macrophage CSF (GMCSF) induced an increased expression of PPAR-{gamma} [8,40]. In addition to PPAR-{gamma} expression being up-regulated after macrophage activation, PPAR-{gamma} activation can itself lead to differentiation of monocytes along the macrophage lineage [41].

One of the first reports to indicate a role for PPAR-{gamma} in inflammation demonstrated that PPAR-{gamma} agonists suppress the production of the inflammatory cytokines interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-{alpha} in stimulated human peripheral blood monocytes [42]. At the same time, Ricote and colleagues demonstrated that PPAR-{gamma} is markedly up-regulated in activated peritoneal macrophages, and that PPAR-{gamma} ligands inhibit the expression of iNOS, gelatinase B and scavenger receptor A genes, in part by antagonising the activities of the transcription factors AP-1, STAT and NF-{kappa}B [39]. In a related study, 12-PGJ2 was found to be a potent inhibitor of iNOS protein expression in stimulated macrophages, and it was suggested that this inhibition may be mediated by modulation of heme oxygenase-1 (HO-1) [43]. However, it has since been demonstrated that 15d-PGJ2-induced HO-1 expression is independent of PPAR-{gamma}, but dependent on oxidative stress [44].

Since these initial observations, other reports have added to characterisation of the expression, regulation and mechanisms of the anti-inflammatory activity of PPAR-{gamma}. Huang and colleagues found that PPAR-{gamma} expression in macrophages is not only up-regulated by IL-4, but that IL-4 also enhances the activation of PPAR-{gamma} via the production of endogenous PPAR-{gamma} ligands such as 13-HODE, 12-HETE, and 15-HETE [45]. Azuma and colleagues demonstrated that 15d-PGJ2 as well as 13-HODE inhibited LPS-induced IL-10 and IL-12 production by macrophages [46]. PPAR-{gamma} activation has been shown to suppress cycloxygenase (COX)-2 expression by preventing activation and translocation of NF-{kappa}B [47,48]. In T cells, PPAR-{gamma} activation inhibits IL-2 production in a mechanism believed to involve transrepression of NFAT [14]. In the rat, PPAR-{gamma} activation has also been reported to down-regulate CCR2, a receptor for monocyte chemoattractant protein-1 (MCP-1), in circulating monocytes [49]. CCAT/enhancer-binding proteins (C/EBPs) up-regulate the transcription of various inflammatory cytokines and acute phase proteins, including IL-1β, IL-6, TNF-{alpha} and COX-2. Takata and colleagues demonstrated that inflammation-induced C/EBP-{delta} expression up-regulates transcription and protein expression of PPAR-{gamma}, which, in turn negatively modulates inflammation through suppression of C/EBP-{delta} via STAT-3 signalling pathways [50]. This negative feedback system may account for the anti-inflammatory action of PPAR-{gamma} ligands. PPAR-{gamma} is not only involved in down-regulation of pro-inflammatory cytokine expression, but also induces apoptosis. It has been reported that PPAR-{gamma} agonists induce apoptosis in TNF-{alpha}/IFN-{gamma}-stimulated macrophages by interfering with the anti-apoptotic NF-{kappa}B signalling pathway [8].

What, then, is the evidence that PPAR-{gamma} agonists exert anti-inflammatory effects in vivo? In 2002, we reported that 15d-PGJ2 reduces the degree of acute inflammation in a rat model of carageenan-induced pleurisy. Similarly, chronic administration of low dose 15d-PGJ2 (30 µg/kg every 48 h) reduces the inflammation and bone erosion associated with a model of collagen-induced arthritis in the rat. This study [51] indicated for the first time that selective PPAR-{gamma} ligands may exert potent anti-inflammatory effects in vivo. As some of the effects of 15d-PGJ2 are, however, not mediated by activation of PPAR-{gamma}, it was important to establish that selective PPAR-{gamma} agonists exert similar effects. Indeed, rosiglitazone also reduces the severity of arthritis (clinical, radiographic, histopathological indicators of inflammation and tissue injury) associated with collagen-II induced arthritis in the rat [52]. Rosiglitazone also causes a dose-related (1–10 mg/kg i.p.) reduction in the paw oedema caused by carrageenan in the rat and, hence, in the degree of acute inflammation [53]. In mice, administration of cerulein causes an acute, severe pancreatitis, which is characterized by expression of adhesion molecules (ICAM-1), excessive neutrophil accumulation within the pancreas, lipid peroxidation and secondary lung injury (acute respiratory distress syndrome). Pre-treatment of mice with rosiglitazone prevented the degree of pancreatic inflammation as well as the associated lung injury [54]. Thus, there is now ample evidence that PPAR- {gamma} ligands and specifically rosiglitazone reduce inflammation in vivo. Interestingly, there is also evidence that PPAR-{gamma} is expressed in human keratinocytes and a number of chemically distinct PPAR-{gamma} ligands (rosiglitazone, ciglitazone, 15d-PGJ2) inhibited the proliferation of normal and psoriatic human keratinocytes in culture [55]. Troglitazone treatment normalized the histological features of psoriatic skin in organ culture and reduced the epidermal hyperplasia of psoriasis in the severe combined immunodeficient mouse and human skin transplant model of psoriasis. Most notably, in patients with psoriasis, troglitazone reduced the degree of inflammation and improved clinical outcome [55]. In a more recent study, rosiglitazone has been reported to attenuate the enhanced keratinocyte motility, increased matrix metalloproteinase production and increased keratinocyte proliferation associated with psoriasis [56]. The authors suggest that interference with these keratinocyte responses may contribute to the previously reported anti-psoriatic activity of TZDs. All of these data support the view that PPAR-{gamma} agonists may be useful in the therapy of inflammatory disorders of the skin and other tissues/organs.


   5. Myocardial ischemia/reperfusion injury
Top
 Abstract
 1. Introduction
 2. Endogenous PPAR-{gamma}...
 3. Synthetic PPAR-{gamma}...
 4. PPAR-{gamma} in inflammation
 5. Myocardial...
6. Ischemia/reperfusion injury...
 7. Shock models
 8. Concluding remarks
 References
 
Using isolated perfused hearts from streptozotocin-induced diabetic rats, Shimabukuro and colleagues found that pre-treatment of animals with the PPAR-{gamma} agonist troglitazone for 6 weeks significantly reduced post-ischemic cardiac dysfunction [57]. In a similar model, treatment of diabetic rats with rosiglitazone for 4 weeks prevented I/R-induced injury and significantly improved functional recovery [58]. The authors showed that this cardioprotective effect is associated with inhibition of the JNK/AP-1 pathway.

The concept that PPAR-{gamma} ligands reduce the tissue injury associated with myocardial I/R is further supported by a number of in vivo studies published in the last few years. In a study conducted to evaluate the effects of troglitazone on the recovery of left ventricular function after acute ischemia in vivo, non-diabetic pigs were treated with troglitazone for 8 weeks followed by regional left ventricular ischemia and reperfusion. When compared to vehicle-treated controls, chronic troglitazone administration significantly improved recovery of left ventricular systolic and diastolic function as well as increasing net myocardial lactate uptake, suggesting enhanced myocardial carbohydrate oxidation [59]. In 2001/2, Wayman and colleagues reported that various chemically distinct agonists of PPAR-{gamma} reduced the infarct size caused by regional myocardial ischemia and reperfusion in the anesthetised rat [60,61]. The TZDs rosiglitazone, ciglitazone and pioglitazone, as well as the prostaglandins 15d-PGJ2 and PGA1, caused a substantial reduction in myocardial infarct size when administered prior to the onset of myocardial ischemia. The reductions in infarct size afforded by the TZDs (rosiglitazone: ~45%; ciglitazone: ~45% and pioglitazone: ~25%) correlated positively with their potency as PPAR-{gamma} agonists in vitro [21], suggesting the reduction in myocardial infarct size afforded by these drugs is, at least in part, due to their ability to activate PPAR-{gamma}. The most pronounced reduction in infarct size (>60%) was, however, observed with 15d-PGJ2. Several mechanisms for the cardioprotective effects of 15d-PGJ2 were suggested: (1) activation of PPAR-{gamma} as well as PPAR-{alpha}; (2) expression of HO-1; and (3) inhibition of the activation of NF-{kappa}B.

The cardioprotective effects of rosiglitazone and pioglitazone have also been reported in two independent studies using rat models of myocardial ischemia and reperfusion [62,63]. In 2001, Yue and colleagues reported that rosiglitazone causes a significant reduction in myocardial infarct size and release of creatinine kinase as well as an improvement in cardiac function [63]. Rosiglitazone also inhibited leukocyte–endothelial cell interaction by regulating the expression of adhesion molecules: rosiglitazone attenuated I/R-induced up-regulation of CD11b/CD18 and down-regulation of L-selectin expression on neutrophils and monocytes, as well as attenuating ICAM-1 expression in the myocardium. In 2003, Ito and colleagues also showed that pre-treatment with pioglitazone for 7 days before coronary ligation and reperfusion results in a significant reduction in myocardial infarct size as well as a reduction in mRNA levels of MCP-1 and ICAM-1 [62].

There is recent evidence that the degree of myocardial I/R-induced injury and contractile impairment is reduced in hypercholesterolemic rabbits chronically treated with rosiglitazone for 5 weeks [64,65]. Most notably, rosiglitazone attenuated the increase in caspase-3 activity as well as the degree of apoptotic cell death in these hearts as determined by TUNEL staining and DNA ladder formation. In addition myocardial ischemia and reperfusion resulted in an increase in p38 phosphorylation and a decrease in ERK1/2 activity and both of these effects were abolished by rosiglitazone. Thus, rosiglitazone not only reduces necrotic cell death but also prevents cardiac myocyte apoptosis by interfering with these signal events leading to the activation of caspase-3 [64].

It should also be noted that, in some studies, PPAR-{gamma} activation failed to provide myocardial protection in ischemia and reperfusion. For example, pre-treatment with rosiglitazone was not protective in a porcine model of myocardial ischemia and reperfusion, whereas the protective effects of troglitazone were attributed to its alpha-tocopherol moiety [66].


   6. Ischemia/reperfusion injury of other organs
Top
 Abstract
 1. Introduction
 2. Endogenous PPAR-{gamma}...
 3. Synthetic PPAR-{gamma}...
 4. PPAR-{gamma} in inflammation
 5. Myocardial...
 6. Ischemia/reperfusion injury...
7. Shock models
 8. Concluding remarks
 References
 
Using PPAR-{gamma} deficient mice and the PPAR-{gamma} agonist rosiglitazone, Nakajima and colleagues were the first to show that PPAR-{gamma} plays an intrinsic protective role in the intestine against I/R injury [67]. In the absence of endogenous PPAR-{gamma}, ischemia and reperfusion of the intestine resulted in aggravated tissue injury, whereas treatment with rosiglitazone inhibited both local and remote organ injury in a dose-dependent manner. This protection appears to be, at least in part, due to inhibition of NF-{kappa}B, as both the transcription factor and its downstream target genes, TNF-{alpha} and ICAM-1, were suppressed by rosiglitazone. In a rat model of I/R-induced intestinal injury, pre-treatment with pioglitazone also inhibited the increase in luminal protein concentration and neutrophil infiltration [68]. To confirm whether the observed beneficial effects of PPAR-{gamma} agonists in I/R of the gut are, in fact, due to activation of PPAR-{gamma}, Cuzzocrea et al. investigated whether the PPAR-{gamma} antagonist, bisphenol A diglycidyl ether (BADGE), attenuates the protection afforded by rosiglitazone and the endogenous agonist 15d-PGJ2 [69]. BADGE abolished the beneficial effects of both PPAR-{gamma} agonists in a rat model of intestinal I/R, confirming that the protective effects of PPAR-{gamma} agonists are secondary to activation of the PPAR-{gamma} receptor.

There is also good evidence that pioglitazone ameliorates the gastric mucosal damage associated with ischemia and reperfusion [70,71]. More recently, the protective effects of endogenous PPAR-{gamma} against gastric mucosal lesions were further demonstrated in a murine model of I/R-induced stomach injury [72]. In this study, animals treated with specific PPAR-{gamma} ligands rosiglitazone, pioglitazone, or troglitazone exhibited dramatic and rapid protection against the gastric injury associated with I/R. In contrast, the gastric damage induced by I/R in PPAR-{gamma} deficient mice was far more severe than that observed in the wild-type controls. PPAR-{gamma} activation significantly inhibited the up-regulation of TNF-{alpha}, ICAM-1, iNOS and apoptosis induced by I/R in the stomach. These data provide substantial evidence for an important role of endogenous PPAR-{gamma} in the pathogenesis of I/R associated injury in the stomach.

In a study conducted to evaluate the role of PPAR-{gamma} on I/R-induced renal injury, Sivarajah and colleagues were the first to demonstrate that PPAR-{gamma} agonists significantly reduce the injury caused by ischemia and reperfusion of the kidney [73]. Ischemia, induced by bilateral clamping of the renal pedicles, followed by reperfusion resulted in a significant degree of renal injury and dysfunction and neutrophil infiltration. These indicators of renal injury/dysfunction were ameliorated in rats pre-treated with rosiglitazone or ciglitazone.

In a murine model of lung ischemia and reperfusion, pre-treatment with troglitazone provided potent protection against ischemic pulmonary injury [74]. Another recently published study has also reported the protective effects of pioglitazone administration on lung I/R injury in rats [75]. Pre-ischemic pioglitazone treatment significantly reduced the increase in lung microvascular permeability, tissue lipid peroxidation and neutrophil infiltration caused by reperfusion.


   7. Shock models
Top
 Abstract
 1. Introduction
 2. Endogenous PPAR-{gamma}...
 3. Synthetic PPAR-{gamma}...
 4. PPAR-{gamma} in inflammation
 5. Myocardial...
 6. Ischemia/reperfusion injury...
 7. Shock models
8. Concluding remarks
 References
 
In a recent study, Guyton et al. investigated whether the PPAR-{gamma} agonists 15d-PGJ2 and troglitazone block LPS, Escherichia coli- (EC) or Staphylococcus aureus- (SA) induced mediator production in rat peritoneal macrophages [76]. They found that both agonists inhibited thromboxane production, whereas only 15d-PGJ2 inhibited NO production in macrophages stimulated with each bacterial product. Differential effects on cell signalling events were observed between the agonists. 15d-PGJ2 suppressed LPS-, E. Coli-, and SA-induced activation of the MAPKs extracellular signal-regulated receptor kinases 1 and 2 (ERK1/2) and blocked I{kappa}B{alpha} degradation, preventing translocation of NF-{kappa}B. In contrast, troglitazone had no significant effect on either signalling protein, suggesting that PPAR-{gamma}-independent effects of 15d-PGJ2 may contribute to its more potent anti-inflammatory effects. Several investigations have since provided evidence that PPAR-{gamma} ligands reduce the multiple organ injury/dysfunction caused by shock. In a model of Gram-negative shock, pre-treatment of rats with 15d-PGJ2 prevented the multiple organ failure caused by endotoxin [77,78]. Endotoxin for 6 h (6 mg/kg i.v. EC LPS) resulted in a significant degree of renal, hepatic and pancreatic dysfunction/injury, which was attenuated by 15d-PGJ2. The beneficial effects afforded by 15d-PGJ2 were reduced by the PPAR-{gamma} antagonist GW9662, demonstrating that the mechanisms of the protective effects of 15d-PGJ2 are, at least in part, PPAR-{gamma} dependent. In a model of polymicrobial shock, pre-treatment with 15d-PGJ2 attenuated the organ injury/dysfunction caused by co-administration of LPS and peptidoglycan in the rat [79]. The protection afforded by the cyclopentenone prostaglandin was reduced by GW9662. Similarly, treatment of mice with rosiglitazone reduced the development of zymosan-induced multiple organ injury and inflammation, an effect which was also reversed by GW9662 [80]. In a rat model of polymicrobial sepsis induced by cecal ligation and puncture, treatment with 15d-PGJ2 or ciglitazone ameliorated hypotension and mortality, blunted cytokine production, and reduced neutrophil infiltration [81]. The beneficial effects of these PPAR-{gamma} ligands were reported to be secondary to a negative modulation of NF-{kappa}B and AP-1 signal transduction pathways.

In a study conducted to evaluate the role of PPAR-{gamma} in hemorrhagic shock, 15d-PGJ2 attenuated the renal, hepatic, lung and intestinal injury/dysfunction associated with hemorrhage and resuscitation [82]. In this model, GW9662 not only reversed the protective effects afforded by 15d-PGJ2, but augmented the degree of liver injury caused by hemorrhage and resuscitation [83]. This finding, therefore, indicates that hemorrhage and resuscitation results in the release of endogenous PPAR-{gamma} ligands and that the amounts of these ligands released are sufficient to protect the liver against the organ injury associated with hemorrhagic shock.


   8. Concluding remarks
Top
 Abstract
 1. Introduction
 2. Endogenous PPAR-{gamma}...
 3. Synthetic PPAR-{gamma}...
 4. PPAR-{gamma} in inflammation
 5. Myocardial...
 6. Ischemia/reperfusion injury...
 7. Shock models
 8. Concluding remarks
References
 
In the past few years, we have seen a very substantial increase in our understanding of the effects of selective PPAR-{gamma} ligands, particularly of the TZDs [84–87]. We know today that the therapeutic effects of PPAR-{gamma} ligands reach far beyond their use as insulin-sensitizers, as many of these agents exert beneficial effects in conditions associated with I/R and inflammation. Currently, TZDs are used in the therapy of patients with type II diabetes mellitus, who have a significantly higher incidence of acute myocardial infarction. Thus, the finding that glitazones reduce myocardial infarct size when given prior to the onset of an ischemic episode (at least in animals) may well be of clinical importance. Many studies now show that glitazones exert potent anti-inflammatory effects in a number of animal models of acute and chronic inflammation as well as shock. The mechanisms underlying these anti-inflammatory effects or indeed the mechanisms underlying the anti-ischemic effects of these agents are not entirely clear. Nevertheless, these findings may stimulate the use of glitazones in clinical conditions associated with local or systemic inflammation. Most notably, there is already evidence that troglitazone reduces the clinical sequelae of psoriasis and clinical trials evaluating the effects of rosiglitazone in this chronic skin disorder are in progress. It is a hope that the efforts made by basic scientists in the last few years will result in the use of glitazones and other PPAR-{gamma} ligands in conditions associated with I/R injury, inflammation and shock.


   Notes
 
Time for primary review 20 days


   References
Top
 Abstract
 1. Introduction
 2. Endogenous PPAR-{gamma}...
 3. Synthetic PPAR-{gamma}...
 4. PPAR-{gamma} in inflammation
 5. Myocardial...
 6. Ischemia/reperfusion injury...
 7. Shock models
 8. Concluding remarks
 References
 

  1. Evans R.M. The steroid and thyroid hormone receptor superfamily. Science (1988) 240:889–895.[Abstract/Free Full Text]
  2. Moras D., Gronemeyer H. The nuclear receptor ligand-binding domain: structure and function. Curr. Opin. Cell Biol. (1998) 10:384–391.[CrossRef][ISI][Medline]
  3. Greene M.E., Blumberg B., McBride O.W., Yi H.F., Kronquist K., Kwan K., et al. Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Expr. (1995) 4:281–299.[Medline]
  4. Sher T., Yi H.F., McBride O.W., Gonzalez F.J. cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor. Biochemistry (1993) 32:5598–5604.[CrossRef][ISI][Medline]
  5. Yoshikawa T., Brkanac Z., Dupont B.R., Xing G.Q., Leach R.J., Detera-Wadleigh S.D. Assignment of the human nuclear hormone receptor, NUC1 (PPARD), to chromosome 6p21.1–p21.2. Genomics (1996) 35:637–638.[CrossRef][ISI][Medline]
  6. Desvergne B., Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr. Rev. (1999) 20:649–688.[Abstract/Free Full Text]
  7. Braissant O., Foufelle F., Scotto C., Dauca M., Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology (1996) 137:354–366.[Abstract]
  8. Chinetti G., Griglio S., Antonucci M., Torra I.P., Delerive P., Majd Z., et al. Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J. Biol. Chem. (1998) 273:25573–25580.[Abstract/Free Full Text]
  9. Chinetti G., Fruchart J.C., Staels B. Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation. Inflamm. Res. (2000) 49:497–505.[CrossRef][ISI][Medline]
  10. Clark R.B., Bishop-Bailey D., Estrada-Hernandez T., Hla T., Puddington L., Padula S.J. The nuclear receptor PPAR gamma and immunoregulation: PPAR gamma mediates inhibition of helper T cell responses. J. Immunol. (2000) 164:1364–1371.[Abstract/Free Full Text]
  11. Faveeuw C., Fougeray S., Angeli V., Fontaine J., Chinetti G., Gosset P., et al. Peroxisome proliferator-activated receptor gamma activators inhibit interleukin-12 production in murine dendritic cells. FEBS Lett. (2000) 486:261–266.[CrossRef][ISI][Medline]
  12. Gosset P., Charbonnier A.S., Delerive P., Fontaine J., Staels B., Pestel J., et al. Peroxisome proliferator-activated receptor gamma activators affect the maturation of human monocyte-derived dendritic cells. Eur. J. Immunol. (2001) 31:2857–2865.[CrossRef][ISI][Medline]
  13. Marx N., Sukhova G., Murphy C., Libby P., Plutzky J. Macrophages in human atheroma contain PPARgamma: differentiation-dependent peroxisomal proliferator-activated receptor gamma(PPARgamma) expression and reduction of MMP-9 activity through PPARgamma activation in mononuclear phagocytes in vitro. Am. J. Pathol. (1998) 153:17–23.[Abstract/Free Full Text]
  14. Yang X.Y., Wang L.H., Chen T., Hodge D.R., Resau J.H., DaSilva L., et al. Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. PPARgamma co-association with transcription factor NFAT. J. Biol. Chem. (2000) 275:4541–4544.[Abstract/Free Full Text]
  15. Gurnell M. PPARgamma and metabolism: insights from the study of human genetic variants. Clin. Endocrinol. (Oxf) (2003) 59:267–277.[CrossRef][Medline]
  16. Dubuquoy L., Dharancy S., Nutten S., Pettersson S., Auwerx J., Desreumaux P. Role of peroxisome proliferator-activated receptor gamma and retinoid X receptor heterodimer in hepatogastroenterological diseases. Lancet (2002) 360:1410–1418.[CrossRef][ISI][Medline]
  17. Kodera Y., Takeyama K., Murayama A., Suzawa M., Masuhiro Y., Kato S. Ligand type-specific interactions of peroxisome proliferator-activated receptor gamma with transcriptional coactivators. J. Biol. Chem. (2000) 275:33201–33204.[Abstract/Free Full Text]
  18. Li M., Pascual G., Glass C.K. Peroxisome proliferator-activated receptor gamma-dependent repression of the inducible nitric oxide synthase gene. Mol. Cell Biol. (2000) 20:4699–4707.[Abstract/Free Full Text]
  19. Chung S.W., Kang B.Y., Kim S.H., Pak Y.K., Cho D., Trinchieri G., et al. Oxidized low density lipoprotein inhibits interleukin-12 production in lipopolysaccharide-activated mouse macrophages via direct interactions between peroxisome proliferator-activated receptor-gamma and nuclear factor-kappa B. J. Biol. Chem. (2000) 275:32681–32687.[Abstract/Free Full Text]
  20. Desreumaux P., Dubuquoy L., Nutten S., Peuchmaur M., Englaro W., Schoonjans K., et al. Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies. J. Exp. Med. (2001) 193:827–838.[Abstract/Free Full Text]
  21. Willson T.M., Brown P.J., Sternbach D.D., Henke B.R. The PPARs: from orphan receptors to drug discovery. J. Med. Chem. (2000) 43:527–550.[CrossRef][ISI][Medline]
  22. Forman B.M., Tontonoz P., Chen J., Brun R.P., Spiegelman B.M., Evans R.M. 15-deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell (1995) 83:803–812.[CrossRef][ISI][Medline]
  23. Fitzpatrick F.A., Wynalda M.A. Albumin-catalyzed metabolism of prostaglandin D2. Identification of products formed in vitro. J. Biol. Chem. (1983) 258:11713–11718.[Abstract/Free Full Text]
  24. Kliewer S.A., Lenhard J.M., Willson T.M., Patel I., Morris D.C., Lehmann J.M. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell (1995) 83:813–819.[CrossRef][ISI][Medline]
  25. Powell W.S. 15-deoxy-delta12,14-PGJ2: endogenous PPARgamma ligand or minor eicosanoid degradation product? J. Clin. Invest. (2003) 112:828–830.[CrossRef][ISI][Medline]
  26. Bell-Parikh L.C., Ide T., Lawson J.A., McNamara P., Reilly M., FitzGerald G.A. Biosynthesis of 15-deoxy-delta12,14-PGJ2 and the ligation of PPARgamma. J. Clin. Invest. (2003) 112:945–955.[CrossRef][ISI][Medline]
  27. Chawla A., Barak Y., Nagy L., Liao D., Tontonoz P., Evans R.M. PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation. Nat. Med. (2001) 7:48–52.[CrossRef][ISI][Medline]
  28. Rossi A., Kapahi P., Natoli G., Takahashi T., Chen Y., Karin M., et al. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase. Nature (2000) 403:103–108.[CrossRef][Medline]
  29. Straus D.S., Pascual G., Li M., Welch J.S., Ricote M., Hsiang C.H., et al. 15-deoxy-delta 12,14-prostaglandin J2 inhibits multiple steps in the NF-kappa B signaling pathway. Proc. Natl. Acad. Sci. U. S. A (2000) 97:4844–4849.[Abstract/Free Full Text]
  30. Berger J., Bailey P., Biswas C., Cullinan C.A., Doebber T.W., Hayes N.S., et al. Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma: binding and activation correlate with antidiabetic actions in db/db mice. Endocrinology (1996) 137:4189–4195.[Abstract]
  31. Hauner H. The mode of action of thiazolidinediones. Diabetes Metab. Res. Rev. (2002) 18(Suppl. 2):S10–S15.[CrossRef][ISI][Medline]
  32. Miyazaki Y., Glass L., Triplitt C., Matsuda M., Cusi K., Mahankali A., et al. Effect of rosiglitazone on glucose and non-esterified fatty acid metabolism in Type II diabetic patients. Diabetologia (2001) 44:2210–2219.[CrossRef][ISI][Medline]
  33. Miyazaki Y., Mahankali A., Matsuda M., Glass L., Mahankali S., Ferrannini E., et al. Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone. Diabetes Care (2001) 24:710–719.[Abstract/Free Full Text]
  34. Miyazaki Y., Mahankali A., Matsuda M., Mahankali S., Hardies J., Cusi K., et al. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J. Clin. Endocrinol. Metab. (2002) 87:2784–2791.[Abstract/Free Full Text]
  35. Nolan J.J., Ludvik B., Beerdsen P., Joyce M., Olefsky J. Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N. Engl. J. Med. (1994) 331:1188–1193.[Abstract/Free Full Text]
  36. Miyazaki Y., Matsuda M., DeFronzo R.A. Dose–response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes. Diabetes Care (2002) 25:517–523.[Abstract/Free Full Text]
  37. Yki-Jarvinen H. Thiazolidinediones. N. Engl. J. Med. (2004) 351:1106–1118.[Free Full Text]
  38. von Knethen A., Brune B. PPARgamma–an important regulator of monocyte/macrophage function. Arch. Immunol. Ther. Exp. (Warsz.) (2003) 51:219–226.[Medline]
  39. Ricote M., Li A.C., Willson T.M., Kelly C.J., Glass C.K. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature (1998) 391:79–82.[CrossRef][Medline]
  40. Ricote M., Huang J., Fajas L., Li A., Welch J., Najib J., et al. Expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein. Proc. Natl. Acad. Sci. U. S. A (1998) 95:7614–7619.[Abstract/Free Full Text]
  41. Tontonoz P., Nagy L., Alvarez J.G., Thomazy V.A., Evans R.M. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell (1998) 93:241–252.[CrossRef][ISI][Medline]
  42. Jiang C., Ting A.T., Seed B. PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature (1998) 391:82–86.[CrossRef][Medline]
  43. Colville-Nash P.R., Qureshi S.S., Willis D., Willoughby D.A. Inhibition of inducible nitric oxide synthase by peroxisome proliferator-activated receptor agonists: correlation with induction of heme oxygenase 1. J. Immunol. (1998) 161:978–984.[Abstract/Free Full Text]
  44. Gong P., Stewart D., Hu B., Li N., Cook J., Nel A., et al. Activation of the mouse heme oxygenase-1 gene by 15-deoxy-delta(12,14)-prostaglandin J(2) is mediated by the stress response elements and transcription factor Nrf2. Antioxid. Redox Signal. (2002) 4:249–257.[CrossRef][ISI][Medline]
  45. Huang J.T., Welch J.S., Ricote M., Binder C.J., Willson T.M., Kelly C., et al. Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. Nature (1999) 400:378–382.[CrossRef][Medline]
  46. Azuma Y., Shinohara M., Wang P.L., Ohura K. 15-deoxy-delta(12,14)-prostaglandin J(2) inhibits IL-10 and IL-12 production by macrophages. Biochem. Biophys. Res. Commun. (2001) 283:344–346.[CrossRef][ISI][Medline]
  47. Inoue H., Tanabe T., Umesono K. Feedback control of cyclooxygenase-2 expression through PPARgamma. J. Biol. Chem. (2000) 275:28028–28032.[Abstract/Free Full Text]
  48. Maggi L.B. Jr., Sadeghi H., Weigand C., Scarim A.L., Heitmeier M.R., Corbett J.A. Anti-inflammatory actions of 15-deoxy-delta 12,14-prostaglandin J2 and troglitazone: evidence for heat shock-dependent and -independent inhibition of cytokine-induced inducible nitric oxide synthase expression. Diabetes (2000) 49:346–355.[CrossRef][ISI][Medline]
  49. Ishibashi M., Egashira K., Hiasa K., Inoue S., Ni W., Zhao Q., et al. Antiinflammatory and antiarteriosclerotic effects of pioglitazone. Hypertension (2002) 40:687–693.[Abstract/Free Full Text]
  50. Takata Y., Kitami Y., Yang Z.H., Nakamura M., Okura T., Hiwada K. Vascular inflammation is negatively autoregulated by interaction between CCAAT/enhancer-binding protein-delta and peroxisome proliferator-activated receptor-gamma. Circ. Res. (2002) 91:427–433.[Abstract/Free Full Text]
  51. Cuzzocrea S., Wayman N.S., Mazzon E., Dugo L., Di Paola R., Serraino I., et al. The cyclopentenone prostaglandin 15-deoxy-delta(12,14)-prostaglandin J(2) attenuates the development of acute and chronic inflammation. Mol. Pharmacol. (2002) 61:997–1007.[Abstract/Free Full Text]
  52. Cuzzocrea S., Mazzon E., Dugo L., Patel N.S., Serraino I., Di Paola R., et al. Reduction in the evolution of murine type II collagen-induced arthritis by treatment with rosiglitazone, a ligand of the peroxisome proliferator-activated receptor gamma. Arthritis Rheum. (2003) 48:3544–3556.[CrossRef][ISI][Medline]
  53. Cuzzocrea S., Pisano B., Dugo L., Ianaro A., Maffia P., Patel N.S., et al. Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute inflammation. Eur. J. Pharmacol. (2004) 483:79–93.[CrossRef][ISI][Medline]
  54. Cuzzocrea S., Pisano B., Dugo L., Ianaro A., Britti D., Patel N.S., et al. Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-gamma, reduces acute pancreatitis induced by cerulein. Intensive Care Med. (2004) 30:951–956.[CrossRef][ISI][Medline]
  55. Ellis C.N., Varani J., Fisher G.J., Zeigler M.E., Pershadsingh H.A., Benson S.C., et al. Troglitazone improves psoriasis and normalizes models of proliferative skin disease: ligands for peroxisome proliferator-activated receptor-gamma inhibit keratinocyte proliferation. Arch. Dermatol. (2000) 136:609–616.[Abstract/Free Full Text]
  56. Bhagavathula N., Nerusu K.C., Lal A., Ellis C.N., Chittiboyina A., Avery M.A., et al. Rosiglitazone inhibits proliferation, motility, and matrix metalloproteinase production in keratinocytes. J. Invest. Dermatol. (2004) 122:130–139.[CrossRef][ISI][Medline]
  57. Shimabukuro M., Higa S., Shinzato T., Nagamine F., Komiya I., Takasu N. Cardioprotective effects of troglitazone in streptozotocin-induced diabetic rats. Metabolism (1996) 45:1168–1173.[CrossRef][ISI][Medline]
  58. Khandoudi N., Delerive P., Berrebi-Bertrand I., Buckingham R.E., Staels B., Bril A. Rosiglitazone, a peroxisome proliferator-activated receptor-gamma, inhibits the Jun NH(2)-terminal kinase/activating protein 1 pathway and protects the heart from ischemia/reperfusion injury. Diabetes (2002) 51:1507–1514.[CrossRef][ISI][Medline]
  59. Zhu P., Lu L., Xu Y., Schwartz G.G. Troglitazone improves recovery of left ventricular function after regional ischemia in pigs. Circulation (2000) 101:1165–1171.[Abstract/Free Full Text]
  60. Thiemermann C., Wayman N.S. Menarini academy cardiovascular research awards in basic science 2001: ligands of the orphan receptor peroxisome-proliferator activator-gamma reduce myocardial infarct size. Med. Sci. Monit. (2001) 7:787–789.[Medline]
  61. Wayman N.S., Hattori Y., McDonald M.C., Mota-Filipe H., Cuzzocrea S., Pisano B., et al. Ligands of the peroxisome proliferator-activated receptors (PPAR-gamma and PPAR-alpha) reduce myocardial infarct size. FASEB J. (2002) 16:1027–1040.[Abstract/Free Full Text]
  62. Ito H., Nakano A., Kinoshita M., Matsumori A. Pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, attenuates myocardial ischemia/reperfusion injury in a rat model. Lab. Invest. (2003) 83:1715–1721.[CrossRef][ISI][Medline]
  63. Yue Tl.T.L., Chen J., Bao W., Narayanan P.K., Bril A., Jiang W., et al. In vivo myocardial protection from ischemia/reperfusion injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Circulation (2001) 104:2588–2594.[Abstract/Free Full Text]
  64. Liu H.R., Tao L., Gao E., Lopez B.L., Christopher T.A., Willette R.N., et al. Anti-apoptotic effects of rosiglitazone in hypercholesterolemic rabbits subjected to myocardial ischemia and reperfusion. Cardiovasc. Res. (2004) 62:135–144.[Abstract/Free Full Text]