Artículo destacado

Drug News & Perspectives
Vol. 17, No. 4, 2004, pp. 229-236
ISSN 0214-0934
Copyright 2004 Prous Science, S.A.
CCC: 0214-0934/2004
http://www.prous.com

LOOKING AHEAD

Type 2 diabetics are at high risk for vascular disease and could benefit from antiinflammatory actions of PPARγ agonists on atherosclerosis, myocardial ischemia and cerebral ischemia.

Antiinflammatory Properties of PPARγ Agonists Following Ischemia

by Sophia Sundararajan and Gary E. Landreth

Summary

Ischemic disease is a leading cause of death and disability worldwide, and its incidence is expected to increase as the population ages. One population at particularly high risk of developing ischemia is patients with diabetes. Type 2 diabetes is associated with a marked increase in atherosclerosis, stroke and heart attack. Furthermore, the outcome following stroke and heart attack in diabetics is worse than in nondiabetic patients. In recent years, peroxisome proliferator-activated receptor (PPAR) agonists have been found to have potent antiinflammatory actions and have emerged as potential therapies for atherosclerosis and ischemia. The use of these agents is particularly attractive, since two PPARγ agonists, pioglitazone (Actos^TM) and rosiglitazone (Avandia^TM), are already used chronically to treat diabetes. In this article we review the role of inflammation in ischemic disease and the biology of PPARs, and summarize the evidence that PPARγ ligands suppress inflammation with an emphasis on atherosclerosis, and cerebral and myocardial ischemia. © 2004 Prous Science. All rights reserved.

Inflammation plays an important role in the generation of injury in acute ischemia, exacerbating the effects of the ischemic insult. Soon after the onset of ischemia, leukocytes and endothelial cells become activated and increase expression of a variety of adhesion molecules. Neutrophils form loose interactions with one such molecule on endothelial cells, P-selectin. This interaction allows leukocytes to roll along the surface of the vessel and brings them into close proximity with other adhesion molecules. β₂-Integrins expressed by activated neutrophils bind intracellular adhesion molecule (ICAM) on the surface of activated endothelium, resulting in firm adhesion. As a consequence, leukocytes become trapped in the microvasculature and obstruct residual blood flow, exacerbating ischemia. Subsequently, neutrophils transmigrate into brain parenchyma. Similar mechanisms utilizing vascular cell adhesion molecule (VCAM) also mediate adhesion and transmigration of monocytes.^1-3 Once within the parenchyma, leukocytes are attracted to the site of ischemia by chemokines such as monocyte chemoattractant protein (MCP-1).^4-7 Strategies that target neutrophils attenuate ischemic injury; for example, antibodies against ICAM reduce cerebral infarction size and improve neurolo-gic function in rats,⁸ and antibodies directed against β₂ integrins limit myocardial infarction size.^3,9-11

Activated leukocytes within ischemic tissue mediate further injury through the release of reactive oxygen species, cytokines and other toxic metabolites. Proinflammatory cytokines are released following both cerebral and myocardial ischemia.^12-14 Antagonism of these cytokines in stroke reduces infarction size.^15,16 In addition, ischemia leads to increased expression of inducible nitric oxide synthase (iNOS). In cerebral ischemia, an iNOS inhibitor decreases infarct size by 33%, and mice that do not express iNOS exhibit reduced infarct size when compared with wild-type controls.^17,18 While low doses of nitric oxide may be beneficial in myocardial ischemia,¹⁹ high doses contribute to myocardial injury.^20-22 Cyclooxygen-ase-2 (COX-2), the rate-limiting enzyme for prostanoid synthesis, is associated with the production of free radicals and toxic prostanoids and is induced during inflammation, and cerebral and myocardial ischemia.^17,23 Cerebral infarction size is reduced by a selective COX-2 inhibitor in rats.¹⁷ Animals treated with a selective COX-2 inhibitor have reduced myocardial infarction size and improved left ventricular end-diastolic and systolic pressure.²³ Some concern has been raised that COX-2 inhibitors may increase the incidence of thrombotic events in patients; however, analysis of large clinical trial databases that contain more than 37,000 patients shows no evidence of increased risk for cerebro- or cardiovascular thrombotic events.²⁴

While inflammation worsens injury secondary to ischemia, the role of inflammation during recovery from ischemia is less clear. Matrix metalloproteinases and cytokines may help organize astrocytic scar tissue and promote reorganization of the brain following ischemic stroke.^15,25 Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), two proinflammatory cytokines, appear to be important regulators of cardiac repair following myocardial ischemia.^3,26 It is possible that the degree of inflammation and the timing of inflammation following ischemia are important determinants of functional recovery.

PPARγ ligands

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors structurally related to the steroid and retinoic acid receptor families.²⁷ When bound to ligands, PPARs form heterodimers with retinoic X receptors (RXRs) and then bind to PPAR response elements within the promoters of target genes, thereby influencing gene expression (Fig. 1). There are three PPAR isoforms (PPARα, -β and -γ), each of which is differentially expressed and displays a distinct pattern of ligand specificity. The PPARγ isoform is abundantly expressed in adipocytes, where it regulates expression of several genes critical to lipid metabolism.²⁸ PPARγ ligands enhance insulin-mediated glucose uptake into skeletal muscle,^29,30 thereby reversing the primary deficit in insulin resistance and decreasing serum glucose levels in type 2 diabetic patients. It should be noted that in rodents and humans without insulin resistance, PPARγ ligands do not lower serum glucose^31,32 and that these agents are not associated with significant hypoglycemia. PPARγ ligands im-prove hypertension and lipid profiles,³³ which, in addition to diabetes, are significant risk factors for vascular disease and subsequent ischemia. The thiazolidinediones, a class of PPARγ agonists, include two agents, pioglitazone and rosiglitazone, that are in clinical use for type 2 diabetes. Although another thiazolidinedione, troglitazone, was removed from the market because of hepatotoxicity, there is no evidence that either pioglitazone or rosiglitazone have similar side effects, despite 4 years of widespread clinical use. In addition, experimental evidence indicates that the hepatotoxic effects are unique to troglitazone.³⁴

Fig. 1. Peroxisome proliferator-activated receptor γ (PPARγ) ligands inhibit proinflammatory gene expression. Ligands of PPARγ include 15δ-PGJ2, docosahexaenoic acid (DHA), nonsteroidal antiinflammatory drugs (NSAIDs) and thiazolidinediones (TZDs). Once inside cells, these ligands bind PPARγ/retinoic X receptor (RXR) heterodimers. Binding of PPARγ ligands changes the conformation of the heterodimers, displacing corepressors and allowing coactivator proteins to bind PPARγ/RXR. This multimeric complex then inhibits the actions of several transcription factors that control the expression of proinflammatory genes.

PPARγ agonists and inflammation

It has become clear that PPARγ ligands also suppress inflammation.³⁵ PPARγ is expressed principally by macrophages, dendritic cells and both B and T lymphocytes.^28,36-41 Importantly, there are now several examples of increased PPARγ expression in inflammatory disease.^42-47 Increased PPARγ expression has been seen in smooth muscle cells following balloon injury,⁴⁸ in macrophages within atherosclerotic plaques and in blood vessels of spontaneously hypertensive rats.⁴⁹

It is now clear that PPARγ ligands regulate the expression of adhesion molecules, cytokines, chemokines and other proteins that participate in the inflammatory response to injury. PPARγ ligands inhibit increases in ICAM and VCAM^50,51 and suppress expression of proinflammatory cyto-kines such as TNF-γ, IL-1β and IL-6.^35,52 In addition, iNOS,^53-55 COX-2,⁵⁶ MMP^57-59 and MCP-1⁵⁹ expression are also reduced by PPARγ ligands.

PPARγ ligands may influence inflammatory gene expression through multiple mechanisms (Fig. 2). Some of the antiinflammatory effects of PPARγ ligands may be secondary to the induction of liver X receptor-α (LXRα). PPARγ activation increases the expression of LXRα,⁶⁰ which regulates the expression of inflammatory mediators such as iNOS, COX-2 and a proinflammatory cytokine, IL-6.⁶¹ Further-more, LXRα agonists reduce inflammation in animal models of contact dermatitis and atherosclerotic lesions. These effects are LXRα dependent, as they are not seen in LXRα knockout animals.⁶¹ PPARγ ligands transrepress the activities of several transcription factors that modulate inflammatory responses including nuclear factor-κB (NF-κB), signal transducers and activators of transcription, activator protein 1⁴⁴ and nuclear factor of activated T cells.⁶² Agonist-induced activation of PPARγ is required for effective transrepression. Transrepression may occur through multiple mechanisms including competition for limited co-activator proteins or direct binding and inhibition of transcription factors.³⁵

Fig. 2. Mechanisms of peroxisome proliferator-activated receptor γ (PPARγ) agonist-mediated suppression of inflammatory gene expression. Thiazolidinediones (TZDs) inhibit the actions of nuclear factor-κB (NF-κB), AP-1, STATs and NFAT through a PPARγ-dependent mechanism. In addition, PPARγ activation results in the upregulation of a transcription factor, LXRα, which also acts to suppress inflammatory gene expression. Additional antiinflammatory consequences of PPARγ activation may also occur. The TZDs and 15Δ-PGJ2 (PGJ2) also exhibit receptor-independent actions. High doses of TZD can suppress inflammatory gene expression through their capacity to activate the PPARδ isoform. It is unclear if this PPARδ-mediated suppression of inflammation involves the same transcription factors as PPARγ activation. PGJ2 is able to directly inhibit the function of NF-κB, an important proinflammatory transcription factor. It is possible that additional PPARγ-independent actions also suppress inflammation. These PPARγ-dependent and -independent actions of PPARγ ligands lead to reduced expression of a number of genes involved in the inflammatory process, which may contribute to reduced ischemic injury. Abbreviations: AP-1, activator protein 1; STATs, signal transducers and activators of transcription; NFAT, nuclear factor of activated T cells; ICAM, intracellular adhesion molecule; VCAM, vascular cell adhesion molecule; MCP-1, monocyte chemoattractant protein; COX-2, cyclooxygenase-2; iNOS, inducible nitric oxide synthase.

A number of receptor-independent effects of thiazolidinedione PPARγ agonists have been reported. Recog-nition that 15δ-PGJ2, a PPARγ ligand, exerts its antiinflammatory actions through direct inhibition of NF-κB, without binding PPARγ, has forced reevaluation of many reports in the literature.^63,64 PPARγ knockout animals are not viable; therefore, PPARγ-null cell lines and conditional knockout animals have been developed to address the role of PPARγ activation in PPARγ ligand-mediated suppression of inflammatory gene expression. High doses of thiazolidinediones suppress cytokine production and myeloid development as effectively in PPARγ-null embryonic stem cells as in wild-type cells, demonstrating that under these conditions PPARγ activation was not required for these effects.^65,66 On the other hand, single amino acid mutations in PPARγ have been shown to abolish inhibition of the iNOS promotor by PPARγ ligands.⁶⁷ More recently, low doses of rosiglitazone were shown to inhibit expression of lipopolysaccharide and interferon gamma target genes in a PPARγ-dependent fashion in mice with PPARγ null macrophages. However, at high doses rosiglitazone inhibited inflammatory gene expression independently of PPARγ activation, presumably through activation of the PPARδ isoform.⁶⁸

PPARγ agonists and ischemia

Cerebral infarction is the third leading cause of death and the leading cause of disability in the United States, and myocardial infarction is the leading cause of death. Although cerebral and myocardial ischemia are often considered separately, they share common risk factors including the development of atherosclerosis. Furthermore, one of the leading causes of stroke, cardio-embolism, often occurs as a result of coronary atherosclerosis and ischemia. Inflammation plays a key role in the development of atherosclerosis and the response to cerebral and myocardial ischemia. Therefore, antiinflammatory agents are potential therapies for all three diseases. Currently, there is good evidence from animal models supporting the potential utility of PPARγ agonists in the treatment of atherosclerosis and myocardial infarction. The role of PPARγ in ischemic stroke is less clear.

Atherosclerosis

Atherosclerotic plaques are formed by a multistep process that involves the accumulation of lipids and extracellular matrix within the intima of arteries. A local inflammatory response to this deposition is initiated by the activation of macrophages, T cells, and endothelial and smooth muscle cells. Each of these cell types express PPARγ when activated.^44,48,69-71 Activation of micro-glia results in the expression of adhesion molecules, cytokines and other inflammatory mediators that contribute to the recruitment of additional inflammatory cells, the intracellular uptake of lipids such as oxidized low density lipoprotein (OxLDL), the generation of oxidative species and the proliferation of smooth muscle within the atherosclerotic plaque. Many of these events are modulated by PPARγ ligands. Thiazolidinediones interfere with chemoattraction and recruitment of leukocytes to atherosclerotic pla-ques by inhibiting expression of VCAM, ICAM,⁵¹ chemotactic factors such as MCP-1^72,73 and its receptor, CCR2.⁷⁴ PPARγ ligands are postulated to suppress plaque formation through actions on proliferation, cytokine ex-pression by both T cells and monocytes/macrophages and reduced ex-pression of the free radical scavenger enzymes and OxLDL receptor, CD36.⁷¹ In addition, PPARγ agonists impair smooth muscle proliferation and migration. Troglitazone and ro-siglitazone may improve plaque stability though the inhibition of Ets-1 expression.⁴³ This transcription factor regulates expression of metalloproteinases, endopeptidases that have been implicated in plaque rupture. PPARγ activation also diminishes the synthesis and action of thromboxane A₂, a potent inducer of platelet aggregation and vasoconstriction.⁷¹ Animal models of atherosclerosis and data from human trials indicate that PPARγ ligands significantly affect the generation of atherosclerosis. The agonists reduce macrophage accumulation in the plaque, reduce fatty streak formation, improve glucose metabolism in diabetics and enhance reverse cholesterol transport.^51,75 Pioglitazone and troglitazone decrease the intimal and medial thickness of carotid arteries^76,77 and induce apoptosis of neointimal cells.^48,78

Cerebral ischemia

Diabetes and atherosclerosis are important risk factors for stroke. Given the beneficial effects of PPARγ agonists on these risk factors, it is possible that PPARγ agonists reduce the incidence of stroke. However, additional data suggests that PPARγ ligands may also have neuroprotective actions during ischemia. To date, investigation of the effects of PPARγ agonists in stroke has been presented in abstract form only. We and others have found that PPARγ-IR and mRNA are upregulated in the ischemic brain.^79,80 In addition, we have found that the PPARγ ligands troglitazone and pioglitazone both reduce infarction size and im-prove neurologic function when rats are treated prior to middle cerebral artery occlusion (MCAO). Reduction in infarct size is associated with reduced expression of inflammatory mediators such as ICAM and COX-2, suggesting that suppression of inflammatory gene expression may be the mechanism of protection.^81-83 Other groups have also reported decreased infarction size with ciglitazone, pioglitazone and 15δ-PGJ2 following MCAO.^80,84 Interestingly, Shimazu and Greenberg report that they saw a reduction in infarction size in rats subjected to transient but not focal ischemia, suggesting that PPARγ agonists protect the brain from reperfusion injury but not necessarily from ischemia.⁸⁴ In all of these studies, PPARγ ligands were administered prior to MCAO, and no information regarding delayed administration of agents has been reported.

Another PPAR isotype, PPARα, has very recently been shown to protect the brain during cerebral ischemia.⁸⁵ PPARα, like PPARγ, inhibits iNOS,⁷⁰ COX-2,⁷⁰ VCAM⁸⁶ and ICAM expression.⁸⁷ Mice fed fenofibrate, a PPARα ligand, for 14 days prior to MCAO had smaller infarcts. These findings were interpreted as agonist-mediated effects on vascular function.⁸⁵ These investigators also injected fenofibrate 1 and 6 hours after MCAO and were unable to demonstrate neuroprotection. Al- though fenofibrate activates both PPARα and PPARγ, they argue that the reduction in infarct volume is related to PPARα activation, since PPARα-deficient mice do not show neuroprotection following MCAO.

There are several studies of the effects of PPARγ agonists in other cerebral injury paradigms that support the concept that PPARγ agonists would protect the injured brain. For example, in a Parkinson's disease model, Breidert and colleagues found that pioglitazone prevented dopaminergic cell loss in the substantia nigra pars compacta.⁸⁸ PPARγ agonists delay disease onset and reduce severity of symptoms in experimental autoimmune encephalitis, an animal model of multiple sclerosis.^46,89,90 PPARγ agonists also reduce neurotoxicity in primary cortical neuronal cultures exposed to conditioned medium from monocytes and microglia exposed to the fibrillar β-amyloid,⁹¹ suggesting that they may be beneficial in Alzheimer's disease. PPARγ agonists also reduce iNOS expression and cell death following bacterial lipopolysaccharide and interferon gamma into rat cerebellum in vivo.⁵⁴ Troglitazone attenuates cell death of cultured cerebellar granule neurons exposed to glutamate. In addition, the same authors found that troglitazone suppresses low potassium-induced apoptosis. Importantly, these authors found troglitazone to be beneficial, even when administered 2.5 hours after glutamate exposure. At this time, glutamate antagonists are no longer effective; it is assumed, therefore, that troglitazone interferes with later consequences of glutamate exposure.⁹² Troglitazone and 15δ-PGJ2 also protect immortalized hippocampal neurons from glutamate and hydrogen peroxide-mediated injury.⁹³

Myocardial ischemia

Like the incidence of stroke, it is possible that the incidence of myocardial infarction is reduced by treatment with PPARγ agonists. However, recent studies indicate that PPARγ agonists may also have additional protective effects in the setting of acute myocardial ischemia. Wayman et al. demonstrated that PPARγ mRNA is present in the freshly isolated cardiac myocytes and fibroblasts, and in the left and right ventricles of rat heart subjected to coronary artery ligation. Furthermore, they administered one of several PPARγ ligands including rosiglitazone, pioglitazone and 15δ-PGJ2 by intravenous injection 30 minutes prior to artery occlusion and found that they all significantly reduced infarction size, with 15δ-PGJ2 having the most potent effect. None of the drugs had any significant effects on blood pressure. Rats treated with 15δ-PGJ2 had reduced plasma levels of troponin T, iNOS mRNA, protein nitration, MCP-1 mRNA, ICAM- and P-selectin-IR.⁸⁷ These authors also found that treatment with 15δ-PGJ2 substantially reduced levels of IκB-α degradation after ischemia and reperfusion. Heme oxygenase-1 (HO-1), a cardioprotective enzyme, appears to be a mediator of 15δ-PGJ2's actions, since pretreatment with an HO-1 inhibitor abolishes the protective effects of 15δ-PGJ2,⁸⁷ which was interpreted to be due to PPARγ activation. In a separate study Yue and colleagues pretreated rats by feeding them either rosiglitazone or vehicle for 7 days prior to ischemia and found reduction in infarct size in rats treated with rosiglitazone. They also gave intravenous injections of rosiglitazone Þ hour before left coronary artery occlusion and again at the time of reperfusion and found significant reductions in infarction size. The animals that were treated with the PPARγ agonist possessed decreased immuno-reactivity for the macrophage marker ED-1 and reduced neutrophil accumulation within the ischemic myocardium, as measured by myeloperoxidase activity. In addition, the expression of CD11b/CD18 on neutrophils was attenuated in rats receiving rosiglitazone, indicating that there were not as many activated neutrophils in the tissue. Finally, both mRNA and immuno-reactivity for ICAM and MCP-1 were reduced in tissue from rosiglitazone-treated rats.⁹⁴ In the Wayman and Yue studies, the effects of PPARγ agonists are consistent with previously described actions of PPARγ ligands and suggest that protection occurs via suppression of the inflammatory response to ischemia.

There is also evidence that PPARγ agonists may influence tissue remodeling occurring after myocardial infarction. This is important, since the inflammatory process that follows myocardial infarction is felt to be an important contributor to myocardial healing. Mice fed pioglitazone for 4 weeks, beginning 6 hours after myocardial infarction, had better left ventricular function and less left ventricular dilation than rats fed placebo. This occurred despite the fact that infarction size did not differ between the two groups of rats. Improved contractile function was accompanied by a decrease in myocyte hypertrophy, interstitial fibrosis and reduced expression of TNF-α, transforming growth factor-β and MCP-1 genes in the noninfarcted ventricle.⁹⁵

Conclusion

PPARγ agonists are clinically used to improve insulin sensitivity and serum glucose levels in type 2 diabetics. These patients are at high risk for vascular disease and potentially could benefit from antiinflammatory actions of PPARγ agonists on atherosclerosis, myocardial ischemia and cerebral ischemia. It is clear that agents used to protect cells, and especially neurons, from ischemia must be administered very early during ischemia to be effective. Unlike other agents that have been shown in clinical trials not to be effective in reducing injury and improving outcome following ischemic events, PPARγ agonists are used chronically to treat a risk factor for ischemia. Patients taking PPARγ ligands for treatment of diabetes who then suffered an ischemic event could benefit from the protective actions of PPARγ agonists even if pretreatment were required for efficacy, making PPARγ ligands particularly attractive agents in the treatment of ischemia. Furthermore, since use of these agents is not associated with significant hypoglycemia, the potential exists to use these agents in nondiabetic high-risk patients. More work is needed to determine if benefits found in animals are also present in humans; these agents offer promise to mitigate injury by some of the most devastating diseases we face today.

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Sophia Sundararajan,* M.D., Ph.D., is Assistant Professor in the Department of Neurol-ogy, University Hospitals of Cleveland, Cleveland, Ohio, and Gary E. Lan-dreth, Ph.D., is Professor in the Department of Neurosciences, Case Western Reserve University, Cleve-land, Ohio. *Correspondence: Sophia Sundararajan, Department of Neurol-ogy, University Hospitals of Cleveland, 11100 Euclid Ave., Cleveland, Ohio 44106, U.S.A. Tel: +1 216-368-1113, Fax: +1 216-368-1144; E-mail: Sophia. Sundararajan@case.edu.

Drug News & Perspectives Vol. 17, No. 4, 2004, pp. 229-236
ISSN 0214-0934 Copyright 2004 Prous Science, S.A. CCC: 0214 0934/2004 http://www.prous.com

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