© 2001 American Heart Association, Inc.
Editorials |
The Pleiotropic Nature of the Vascular PPAR Gene Regulatory Pathway
From the Center for Cardiovascular Research, Department of Medicine; Departments of Molecular Biology & Pharmacology and Pediatrics, Washington University School of Medicine, St. Louis, Mo.
Correspondence to Daniel P. Kelly, MD, Center for Cardiovascular Research, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8086, St. Louis, MO 63110. E-mail dkelly{at}imgate.wustl.edu
Key Words: nuclear hormone receptors • vascular smooth muscle • growth factors • atherosclerosis
The peroxisome proliferator-activated receptors (PPARs) are a family of ligand-activated transcription factors within the broad nuclear receptor superfamily. Recent evidence indicates that the PPARs play critical regulatory roles in a variety of biologic processes relevant to the heart and vasculature including lipid and energy metabolism, inflammation, and cellular differentiation (reviewed in Desvergne and Wahli1). The PPAR family includes three members encoded by distinct genes: 
, ß (also known as 
or Nuc1), and 
. The three PPARs are distinguished by tissue- and developmental-specific patterns of expression and by the distinct, albeit overlapping, nature of lipid and eicosanoid ligands capable of activating each receptor. For instance, the expression of PPAR is highly adipose-enriched, whereas PPAR is expressed in tissues with high rates of mitochondrial fatty acid oxidation, such as heart and liver. Ligand activation of PPAR leads to obligate heterodimerization with members of the retinoid X receptor (RXR) subfamily and subsequent binding to cognate DNA response elements within target gene promoter regions. The true endogenous PPAR ligands have not been defined with certainty. Long-chain fatty acids activate each of the PPARs to varying degrees suggesting that lipid species serve as cell-specific PPAR ligands. A number of pharmacologically active, PPAR-specific compounds have been identified leading to a rapidly growing interest in this family of nuclear receptors as targets for drug development. For example, the PPAR activators clofibrate and gemfibrozil have been developed as hypolipidemic agents. Thiazolidinediones (eg, troglitazone, rosiglitazone) are PPAR-specific activators with potent insulin-sensitizing action.
The activity of the PPAR/RXR complex is controlled by an exquisite array of regulatory mechanisms (Figure; reviewed in Barger and Kelly2). The remarkably pleiotropic nature of this regulation allows for the dynamic modulation of PPAR target gene expression across a wide response range in a cell-specific manner. First, the nuclear levels of specific PPARs, RXRs, and their cognate ligands determine the amount of heterodimer available for binding to target DNA element sequences. The availability of the RXR ligand 9-cis retinoic acid (RA) also contributes to the degree of PPAR/RXR activation. Second, the engagement of PPAR ligand leads to the recruitment of a coactivator complex containing proteins such as SRC-1, CBP/p300, PBP/TRAP220, and PGC-1. The coactivator complex possesses histone acetyltransferase activity leading to chromatin remodeling and increased transcription of the target gene. Although most of the coactivator proteins are ubiquitously expressed, certain coactivators such as PPAR coactivator 1 (PGC-1) are inducible providing another means of boosting the activity of the PPAR complex in response to physiologic stimuli.3,4 Third, recent studies have shown that the activity of PPAR and PPAR can be regulated by phosphorylation events. Specifically, phosphorylation by extracellular signal–regulated kinase mitogen-activated protein kinase (ERK-MAPK) inhibits the activities of PPAR and .5,6 In contrast, phosphorylation by protein kinase A or p38 MAPK activates PPAR.7,8 This differential regulation of PPAR activity by signal transduction events provides a mechanism for rapid, cell-specific control of PPAR target gene expression by extracellular stimuli (Figure).
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Evidence is emerging that the PPAR regulatory pathway plays a critical role in the regulation of diverse biologic processes within the cardiovascular system.2 PPAR activates the expression of genes involved in the cellular fatty acid utilization pathway in the normal heart.2 In contrast to PPAR, PPAR is not enriched in the normal adult mammalian heart but has the potential to regulate cardiac metabolism indirectly via its influence on circulating lipid and glucose levels. The biologic function of the PPAR regulatory pathway in the vessel wall is a focus of active investigation. The results of recent studies indicate that PPARs are active in multiple vascular cell types. PPAR and PPAR are expressed in smooth muscle, macrophages, foam cells, and endothelial cells of normal and atherosclerotic vessels in several species including humans.9–14 Vascular PPARß expression has not been extensively characterized to date. Evidence is emerging that PPAR signaling influences the development and severity of vascular disease states such as atherosclerosis and response to injury. Two general strategies have been used to investigate the functional role of PPARs in vascular biology: (1) systemic administration of PPAR activators (activator studies) and (2) evaluation of the vascular phenotype of mice with genetic ablation of PPAR or PPAR genes (loss-of-function studies). Administration of PPAR activators leads to a reduction in the extent of atherosclerosis in murine models of atherosclerosis such as the apolipoprotein E–deficient mouse.15 PPAR activators have also been shown to reduce the neointimal response to injury.14,16,17 The mechanisms involved in these protective effects are unknown, but possible mechanisms include the inhibitory effects of PPAR and on foam cell development, the vascular inflammatory response, or cell adhesion molecule expression.11,13,18 Alternatively, the beneficial effects observed with the PPAR activator studies could reflect indirect effects such as lowering of serum lipids or glucose. PPAR loss-of-function studies have begun to distinguish between direct and indirect effects of the PPARs on the vessel wall but have also unveiled the complexity of this regulatory pathway. An elegant study by Chawla et al19 demonstrated that transplantation of PPAR null bone marrow into LDL receptor–deficient mice fed a Western diet resulted in an increase in aortic atherosclerosis.19 In striking contrast to the results of studies with PPAR-deficient mice, PPAR-null mice exhibit reduced atherosclerosis in an apolipoprotein E–null background.20
In addition to distinguishing between the direct and indirect effects of the PPARs in vivo, it is useful to define the regulation and downstream effects of PPAR and PPAR in distinct cell types isolated from the vasculature. This strategy was used in the study by Fu et al21 in this issue of Circulation Research. The present study provides two new important findings related to vascular PPAR signaling. First, the authors found that platelet-derived growth factor (PDGF) induces PPAR gene expression in human aortic smooth muscle cells in culture. Second, the effect of PDGF on PPAR gene expression was abolished by inhibition of the phosphatidylinositol 3-kinase (PI3-kinase)/Akt signaling pathway. Accordingly, these results have identified another upstream regulatory pathway linked to the PPAR gene regulatory complex.
The results of the study by Fu et al,21 although providing important new information about the regulation of PPAR expression in vascular smooth muscle cells, raise further questions about the role of PPAR signaling as "protector" versus "bad player" in vascular disease. Given that PDGF is generally considered to serve as an upstream trigger of pathologic vascular smooth muscle proliferation, is it possible that under certain circumstances PPAR mediates pathologic responses of the vessel? This conclusion would be premature. Caution must be used in extrapolating the results of cell culture studies to the in vivo scenario. As noted above, previous studies have demonstrated that systemic administration of PPAR agonists is capable of inhibiting vascular intimal hyperplasia. Moreover, the results of activator and loss-of-function studies to date indicate that PPAR serves to reduce the formation of foam cells and atherogenesis in vivo. This seemingly paradoxical collection of results underscores the importance of using multiple complementary experimental strategies to unravel the vascular PPAR regulatory pathway. Systemic administration of PPAR agonists provides information about the in vivo response and the potential for a therapeutic success. However, elucidation of the direct effects of the PPARs on specific vascular cell types will require loss-of-function studies in mice and isolated cell studies. Cell culture studies, such as that reported by Fu et al,21 will continue to serve an important role in the investigation of cell-specific effects and to identify upstream regulatory events relevant to the control of PPAR activity. The molecular dissection of the upstream and downstream components of the vascular PPAR gene regulatory pathway should ultimately lead to the development of novel therapeutic approaches aimed at the inhibition of common disease processes such as atherogenesis and the hyperproliferative response of the vessel wall to injury. Moreover, identification of relevant vascular PPAR target genes should provide insight into genetically determined factors that predispose to common cardiovascular diseases.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
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21.
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