The possible role of peroxisome proliferator-activated receptor gamma in heart failure

Abstract

Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily that heterodimerize with the retinoid X receptor and bind to specific response elements in target gene promoters. PPARs have three isoforms: α, β (or δ) and γ. The prostaglandin D₂ metabolite, 15-deoxy-12,14-prostaglandin J₂, is an endogenous ligand for PPARγ. The antidiabetic thiazolidinediones are synthetic ligands for PPARγ. PPARγ is expressed predominantly in adipose tissue and promotes adipocyte differentiation and glucose homeostasis. PPARγ is also present in various cell types including cardiac myocytes. PPARγ regulates various neurohumoral factors involved in the progression of heart failure; its ligands inhibit cardiac hypertrophy and ischemia-reperfusion injury via, in part, a PPAR-independent pathway. Although experimental studies suggest that PPARγ ligands might have a favourable influence on heart failure, their use in patients with heart failure is limited because of an increase in plasma volume. Further studies are needed to determine whether PPARγ ligands prevent the development of heart disease in clinical settings.

Peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily that heterodimerize with the retinoid X receptor and bind to specific response elements termed PPAR responsive elements in target gene promoters. The PPAR responsive elements are formed by a direct repeat of the hexameric consensus sequence AGGTCA, separated by one spacer nucleotide. These nuclear receptors are ligand-dependent transcription factors, and activation of target gene transcription depends on the binding of the ligand to its receptor. PPARs have three isoforms: α, β/δ and γ. Until relatively recently, PPARα was thought to be limited to the regulation of lipid catabolism and peroxisome proliferation in the liver (1), whereas PPARγ was thought to be involved in adipocyte differentiation and glucose homeostasis (2,3). Although PPARβ/δ is almost ubiquitously expressed (4–6), its roles are poorly understood. Earlier observations indicated that PPARα was present in tissues with a high oxidative capacity, such as liver, kidney and heart, while PPARγ was expressed predominantly in adipose tissue (2,3). More recently, it has been demonstrated that PPARγ is also expressed in many other cell types, such as macrophages, vascular smooth muscle cells, endothelial cells and cardiac myocytes of the cardiovascular system (7–11). Thus, interest in PPARγ’s functions in the cardiovascular system has grown and numerous investigations have focused on PPARγ. In the present review, we introduce the current trends of PPARγ research and discuss the function of PPARγ in the heart.

PPARs: THEIR LIGANDS AND INTRACELLULAR SIGNALLING PATHWAYS

The prostaglandin D₂ metabolite, 15-deoxy-12,14-prostaglandin J₂, was the first endogenous ligand discovered for PPARγ (12,13). Although 15-deoxy-12,14-prostaglandin J₂ is the most potent natural ligand of PPARγ, the extent to which its effects are mediated through PPARγ in vivo remains to be determined. Two components of oxidized low-density lipoprotein, 9-hydroxyoctadecadienoic and 13-hydroxyoctadecadienoic acids, are also potent endogenous activators of PPARγ (14,15). Activation of 12/15-lipoxygenase induced by interleukin-4 also induces the endogenous ligands for PPARγ (16). The antidiabetic thiazolidinediones (TZDs), such as troglitazone, pioglitazone HCl, ciglitazone and rosiglitazone maleate, are synthetic ligands of PPARγ (17,18). TZDs bind PPARγ with various affinities and their insulin-sensitizing effects are exerted by activating PPARγ.

The splice variants of the γ isoform, PPARγ1 and PPARγ2, have been cloned; these two forms differ only in their N-terminal 30 amino acids (19). Although PPARγ1 is expressed in various tissues including liver, kidney, spleen, intestine, muscle, brain and lung, PPARγ2 is predominantly expressed in adipose tissue (4,5,20–22). Both PPARγ isoforms are derived from the same gene with alternative promoter usage and splicing. Like other members of nuclear receptors, PPARs have several modular domains (Figure 1) (23). The N-terminal A/B domain, which contains a ligand-independent activating function-1, is the least conserved. The C domain, which is the best conserved and consists of two zinc fingers, is the DNA-binding domain. The D domain allows for bending or conformational alteration of PPAR. The E/F domain is the ligand-binding domain (LBD). Ligand-dependent transcription requires activating function-2, which is located at the C-terminus of the LBD. Ligand binding by PPARγ is regulated by intramolecular interaction between its N-terminal A/B domain and its C-terminal LBD.

Figure 1).

Schematic representation of the peroxisome proliferator-activated receptors (PPAR). The N-terminal A/B domain contains a ligand-independent activating function (AF)-1. The C domain consists of two zinc fingers and is the DNA-binding domain (DBD). The D domain allows for bending or conformational alteration of PPAR. The E/F domain is the ligand-binding domain (LBD) and ligand-dependent transcription requires AF-2, which is located at the C-terminus of the LBD. Ligand binding by PPARγ is regulated by intramolecular interaction between its N-terminal A/B domain and its C-terminal LBD

The activity of PPARs can be modulated by phosphorylation. PPARγ activity is depressed by phosphorylation of a serine residue (Ser112) in the A/B domain, which is mediated by a member of mitogen-activated protein kinase family, the extracellular signal-regulated protein kinase (24,25). C-Jun N-terminal kinase, another member of the mitogen-activated protein kinase family, also phosphorylates PPARγ at Ser82, reducing the transcriptional activity of PPARγ (26). These modifications may control interactions between PPARγ and coactivators or co-repressors that have been shown to interact with many members of the nuclear receptor family (27). Several lines of evidence have implicated the functional significance of the interaction between nuclear receptors and coactivators in transcriptional activation. The cyclic AMP response element binding protein-binding protein (CBP)/p300 is a transcriptional coactivator of PPARα, PPARγ and nuclear factor kappa B (NF-κB) (28–30). Steroid receptor coactivator-1 (SRC-1) is also a coactivator for both PPARγ and NF-κB (31–33). Puigserver et al (34) reported that both CBP/p300 and SRC-1 interact with the PPARγ:retinoid X receptor heterodimer, and that this interaction was mediated by the initial binding of PPARγ coactivator-1. These findings suggest that nuclear competition for limited amounts of CBP/p300 or SRC-1 may occur between PPARs and other transcription factors.

POSSIBLE ROLE OF PPARγ IN HEART FAILURE

Accumulating evidence suggests that PPARγ ligands have multiple antiatherosclerotic effects, including attenuation of the growth and migration of vascular smooth muscle cells (9,35–39) and endothelial cells (40–42), inhibition of the migration of monocytes (43,44), reduction of inflammatory cytokines from monocytes/macrophages (10,45–47), suppression of vascular cell adhesion molecule-1 and intracellular adhesion molecule-1 expression in endothelial cells (45,48), and increase of cholesterol efflux from foam cells (49–51). Diabetes mellitus is one of the leading and growing causes of coronary artery disease and heart failure. The antiatherosclerotic effects of PPARγ ligands may stabilize atherosclerotic lesions in coronary arteries, which might indirectly result in an improvement of cardiac function in diabetic patients with coronary artery disease.

Left ventricular hypertrophy is an important risk factor for ischemic heart disease and cardiac-related mortality. Insulin resistance and hyperinsulinemia are involved in cardiac hypertrophy (52,53). Yamamoto et al (54) demonstrated that the PPARγ activators, troglitazone and 15-deoxy-Delta-(12,14)-prostaglandin J₂, inhibited cardiac hypertrophy caused by mechanical strain in neonatal cardiac myocytes, mediated, in part, through the NF-κB pathway (54).

The renin-angiotensin system is activated as cardiac function deteriorates, and inhibition of angiotensin-converting enzyme favourably remodels the myocardium in patients with heart failure (55). Asakawa et al (56) reported that PPARγ ligands, such as troglitazone, pioglitazone HCl and rosiglitazone maleate, inhibited angiotensin II-induced cardiac hypertrophy in neonatal rat cardiac myocytes and pressure overload-induced cardiac hypertrophy in mice, suggesting the potential clinical efficacy of TZDs for the prevention of cardiac hypertrophy.

Evidence suggests that the production of tumour necrosis factor-alpha (TNF-α) by cardiac myocytes promotes the development and progression of heart failure (57). Takano et al (11) reported that both PPARα and PPARγ activators inhibited the cardiac expression of TNF-α, in part, through attenuating NF-κB activation, suggesting that treatment with PPAR activators may prevent the development of congestive heart failure. They used only lipopolysaccharide to induce TNF-α production in cardiac myocytes. Because other cytokines, such as interleukin-1beta, interleukin-2 and interleukin-6, are also involved in the pathogenesis of congestive heart failure, further studies are needed to clarify the effects of PPAR activators on the development of heart failure in vivo.

Circulating endothelin-1 (ET-1) levels are correlated with the severity of hemodynamics and symptoms in patients with congestive heart failure (58,59). Preliminary studies (60–62) suggest that glitazones may reduce ET-1 production, which, in turn, may benefit diabetic patients with heart failure. ET-1 has been shown to induce cardiomyocyte growth in vitro (63,64) and to promote collagen synthesis by cardiac fibrosis (65). Recently, Iglarz et al (66) reported that inhibition of cardiac ET-1 production by both PPARα and PPARγ activators was associated with decreased cardiac fibrosis in deoxycorticosterone acetate-salt rats, a model of ET-1-dependent hypertension.

Shimoyama et al (67) suggested that troglitazone may exert inotropic effects in isolated perfused rat hearts, but the exact mechanism of this response still remains controversial. Ghazzi et al (68) reported that troglitazone enhanced cardiac output and stroke volume in patients with type II diabetes, but that this may have been a result of decreased arterial blood pressure and peripheral resistance.

Recently, TZDs and other ligands of PPARγ were thought to reduce tissue injury caused by regional myocardial ischemia and reperfusion in rodents. Ligands of PPARγ caused a substantial reduction in myocardial infarct size when given before onset of myocardial ischemia in the rat (69–71). Rosiglitazone maleate also improved the functional recovery of rat hearts obtained from diabetic animals subjected to global ischemia and reperfusion (72). Although the mechanisms of the cardioprotective effects of TZDs are not entirely clear, they may be due to inhibition of the activation of NF-κB, reduced expression of inducible nitric oxide synthase, monocyte chemoattractant protein-1 and intracellular adhesion molecule-1, and inhibition of Jun NH₂-terminal kinase (70–72). Thus, there is growing evidence that ligands of PPARγ may be useful in the therapy of conditions associated with inflammation and ischemia-reperfusion of the heart and other organs (11,73–82). Shiomi et al (83) reported that pioglitazone HCl administration in mice subjected to infarction significantly reduced left ventricular dysfunction, and that this effect was associated with a decrease in myocyte hypertrophy and interstitial fibrosis, and reduced expression of TNF-α, transforming growth factor-beta and monocyte chemoattractant protein-1. In contrast, Lygate et al (84) did not observe modulation of left ventricular remodelling, and also found increased mortality in rats treated with rosiglitazone maleate when subjected to infarction. However, Frantz et al (85) reported that the administration of pioglitazone HCl had no effect on mortality, left ventricular remodelling, cytokine expression (including TNF-α, interleukin-1β and ET-1), collagen content or endothelial function in mice with chronic myocardial infarction. Thus, further studies are needed to evaluate the effects of TZDs on ischemic myocardium.

The majority of mechanistic and experimental studies suggests that TZDs might favourably influence cardiac hemodynamics in heart failure. However, a large scale clinical trial (86) reported fluid retention and increased plasma volume with glitazone therapy, with an increased incidence of peripheral edema. A large retrospective cohort study (87) suggested that TZD use was predictive of heart failure even after controlling for other variables. This effect may be related to increased endothelial cell permeability induced by glitazone therapy (88,89) and/or, indirectly, the facilitation of insulin’s action in promoting renal sodium retention (90,91). Because an increase in preload may contribute to worsening cardiac function in patients with heart failure, TZDs are contraindicated in patients with heart failure.

CONCLUSIONS

Experimental studies suggest that PPARγ ligands might have a favourable influence on heart failure, as summarized in Figure 2. However, PPARγ ligands increase plasma volume, which contributes to worsening cardiac function. Further studies are needed to clarify the role of PPARγ ligands in heart failure.

Figure 2).

The possible role of peroxisome proliferator-activated receptor gamma (PPARg) on the heart. Experimental evidence suggest that PPARg ligands might have a favourable influence in heart failure. However, PPARg ligands are contraindicated in patients with severe heart failure because these agents increase plasma volume. ET-1 Endothelin-1; ICAM-1 Intracellular adhesion molecule-1; iNOS Inducible nitric oxide synthase; JNK c-Jun N-terminal kinase; MCP-1 Monocyte chemoattractant protein-1; MI Myocardial infarction; NFkB Nuclear factor kappa B; TGFb Transforming growth factor-beta; TNFa Tumour necrosis factor-alpha; ↓ Decreased