PPARs and the cardiovascular system - PubMed (original) (raw)

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PPARs and the cardiovascular system

Milton Hamblin et al. Antioxid Redox Signal. 2009 Jun.

Abstract

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone-receptor superfamily. Originally cloned in 1990, PPARs were found to be mediators of pharmacologic agents that induce hepatocyte peroxisome proliferation. PPARs also are expressed in cells of the cardiovascular system. PPAR gamma appears to be highly expressed during atherosclerotic lesion formation, suggesting that increased PPAR gamma expression may be a vascular compensatory response. Also, ligand-activated PPAR gamma decreases the inflammatory response in cardiovascular cells, particularly in endothelial cells. PPAR alpha, similar to PPAR gamma, also has pleiotropic effects in the cardiovascular system, including antiinflammatory and antiatherosclerotic properties. PPAR alpha activation inhibits vascular smooth muscle proinflammatory responses, attenuating the development of atherosclerosis. However, PPAR delta overexpression may lead to elevated macrophage inflammation and atherosclerosis. Conversely, PPAR delta ligands are shown to attenuate the pathogenesis of atherosclerosis by improving endothelial cell proliferation and survival while decreasing endothelial cell inflammation and vascular smooth muscle cell proliferation. Furthermore, the administration of PPAR ligands in the form of TZDs and fibrates has been disappointing in terms of markedly reducing cardiovascular events in the clinical setting. Therefore, a better understanding of PPAR-dependent and -independent signaling will provide the foundation for future research on the role of PPARs in human cardiovascular biology.

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Figures

FIG. 1.

Schematic view of PPAR action. After a ligand binds to PPAR, PPAR heterodimerizes with the retinoid X receptor (RXR) and then binds to the PPRE. Recruiting coactivators and co-repressors leads to activation and repression of PPAR target genes, respectively.

FIG. 2.

PPARγ ligands. Natural and synthetic agonists bind and activate PPARγ. Natural PPARγ agonists include 15d-PGJ2, fatty acids, oxidatively modified lipids, hydroxyeicosatetraenoic acid, hydroxyoctadecadienoic acid, oxidized phospholipids, lysophosphatidic acid, and nitroalkenes. Synthetic PPARγ agonists include TZDs, GW1929, GW7845, PPARα/γ dual agonists, and PPARα/γ/δ pan agonists. Examples of PPARγ antagonists include BADGE, GW9662, LG100641, PD068235, and SR-202.

FIG. 3.

Schematic view of PPARγ-dependent and -independent signaling pathways. PPARγ ligands can exert their effects in cardiovascular cells through PPARγ-dependent and -independent mechanisms. PPARγ-mediated increases in IRF-1 and GADD45 result in greater VSMC apoptosis. PPARγ-dependent decreases in c-fos expression attenuate VSMC proliferation. Ligand-activated PPARγ inhibits NF-κB transcriptional activity and inflammation in cardiovascular cells. PPARγ ligand–independent signaling can decrease IκB kinase activity, leading to decreased IκBα phosphorylation, NF-κB transcriptional activity, and inflammation. Another example of PPARγ ligand signaling that occurs independent of PPARγ involves nitroalkylation of the p65 subunit and eventual reduction in NF-κB activity and inflammation. Pioglitazone can regulate mitochondrial oxidative capacity and normalize lipid oxidation through direct binding to the mitoNEET protein, independent of PPARγ.

FIG. 4.

Schematic view of PPARγ activation in ECs. Natural or synthetic PPARγ ligands attenuate VEGF-induced Akt phosphorylation, inhibiting EC proliferation and migration. Ligand-activated PPARγ exerts its antiinflammatory effects by inhibiting cytokine-induced NF-κB activation in ECs.

FIG. 5.

Schematic view of PPARγ activation in vascular tone regulation. PPARγ ligands decrease ET-1 and AT-1R expression and increase AT-2R expression. PPARγ ligands stimulate NO release, and NO can activate endothelial cell PPARγ through MAPK. TZDs can also decrease oxidative and nitrative stress.

FIG. 6.

Schematic view of PPARγ activation in VSMCs. In VSMCs, TZDs attenuate growth factor–induced (e.g., AngII) cell migration, proliferation, and fibrosis in either a PPARγ-dependent or -independent manner by interfering with growth factor–stimulated signaling pathways. PPARγ activation exerts antiinflammatory roles by inhibiting the NF-κB pathway; PPARγ activation promotes apoptosis via inducing IRF-1 or GADD45 expression.

FIG. 7.

Schematic view of PPARγ roles in atherosclerosis. PPARγ ligands increase CLA, ABCA1, and ABCG1 expression, leading to improved lipid homeostasis. PPARγ agonists also decrease proinflammatory cytokine and gene expression and increase antiinflammatory cytokine expression. PPARγ ligands increase SR-B expression, which promotes cholesterol efflux. Conversely, PPARγ activation upregulates CD36 expression, resulting in increased oxLDL uptake. Increased oxLDL levels further stimulate PPARγ expression, which leads to increased CD36 expression. Finally, loss of PPARγ increases CCR2 expression and monocyte recruitment.

FIG. 8.

Schematic view of PPARγ roles in the heart. PPARγ agonists are associated with increased myocardial infarction and cardiovascular events in humans. PPARγ agonists decrease ischemia/reperfusion injury and cardiac hypertrophy while increasing contractile function in mice. Administration of PPARγ agonists decreases JNK/AP-1 and NF-κB signaling pathways and increases carbohydrate oxidation in mice. Mice with cardiac-specific PPARγ overexpression show a dilated cardiomyopathy phenotype. Moreover, these mice have increased expression of genes involved in glucose transport and fatty acid utilization. Myocardial PPARγ-knockout mice display characteristics of cardiac hypertrophy and dilated cardiomyopathy along with increased NF-κB activity, decreased Akt phosphorylation, and decreased antioxidant gene expression.

FIG. 9.

Schematic view of PPARα activation in ECs. PPARα activation attenuates NF-κB signaling and transcription in ECs, leading to decreased adhesion-molecule expression and inhibition of leukocyte interaction with ECs. PPARα ligands inhibit ET-1 synthesis by negatively regulating AP-1.

FIG. 10.

Schematic view of PPARα activation in VSMCs. PPARα activation in VSMCs inhibits proliferation and migration by interfering with cdk and β5-integrin signaling pathways. PPARα activation also exerts antiinflammatory roles via inhibiting NF-κB mediated–inflammatory factor release.

FIG. 11.

Schematic view of PPARα ligand roles in macrophages and atherosclerosis. PPARα ligands may prevent atherosclerosis by improving cholesterol homeostasis, decreasing lipid accumulation, and participating in antiinflammatory signaling in macrophages. LDL-R−/− mice transplanted with bone marrow from PPARα−/− mice have increased atherosclerosis, whereas GW7647 decreases lesion development in LDL-R−/− mice. However, PPARα−/−/apoE−/− mice are protected against the development of atherosclerosis.

FIG. 12.

Schematic view of PPARδ roles in atherosclerosis. PPARδ ligands are beneficial against the development of atherosclerosis by regulating lipid homeostasis in humans. PPARδ ligands attenuate the development of atherosclerosis in mice by decreasing inflammatory gene expression and macrophage migration while increasing plasma HDL. Inhibition of EC and macrophage inflammatory gene expression by PPARδ ligands prevents the development of atherosclerosis. However, PPARδ overexpression stimulates VSMC proliferation and macrophage release of inflammatory factors, which may promote atherosclerotic development.

FIG. 13.

Schematic view of PPARδ roles in the heart. PPARδ ligands increase myocardial fatty acid utilization genes. Cardiac-specific PPARδ-knockout mice have decreased myocardial expression of fatty acid oxidation genes along with increased myocardial lipid accumulation, cardiac hypertrophy, and congestive heart failure. Myocardial PPARδ overexpression in mice increases expression of genes involved in glucose utilization, which may prevent further injury after ischemia/reperfusion.

FIG. 14.

Perspective view of PPARs and PPAR ligands in the cardiovascular system. The use of mouse models has shown that PPAR ligands have many beneficial effects in the cardiovascular system. However, PPAR ligand administration (e.g., rosiglitazone) in the clinical setting has not necessarily translated into markedly improved cardiovascular outcomes. Furthermore, some question exists as to whether the beneficial effects of PPAR agonists involve PPAR-dependent signaling. Although the development of animal model systems specifically for studying PPAR agonists and PPAR gain- and loss-of-function has elucidated important findings regarding the molecular mechanisms of cardiovascular disease, certain limitations pertain to the use of mouse models. In many cases, genetically altered murine models do not display characteristics similar to those of humans. Hence, a need exists for using genetically modified animals, such as rabbits, pigs, or monkeys, that have a closer phenotypic resemblance to humans and therefore may be more appropriate for studying PPARs and PPAR agonists in the cardiovascular system.

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PPARs and the cardiovascular system - PubMed (original) (raw)