doi: 10.1161/CIRCRESAHA.107.170233
© 2008 American Heart Association, Inc.
Editorials |
Peroxisome Proliferator-Activated Receptor β/
Goes Vascular
From Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London, Queen Mary University London, UK.
Correspondence to David Bishop-Bailey, Translational Medicine and Therapeutics, William Harvey Research Institute, Barts and the London, Queen Mary University London, Charterhouse Square, London EC1M 6BQ, United Kingdom. E-mail d.bishop-bailey{at}qmul.ac.uk
See related article, pages 193–200
Key Words: PPAR • vascular smooth muscle • endothelial cell • TGFβ
Peroxisome proliferator-activated receptor (PPAR)s are a family of 3 (PPAR
, -β/
, and -
) nuclear receptor/ligand-activated transcription factors that work in concert as heterodimers with the retinoid X receptors.1 In recent years, there has been great scientific and clinical interest in the actions of PPAR and PPAR because they are the molecular targets for the clinically used lipid-lowering fibrates and insulin-sensitizing thiazolidinedione classes of drugs, respectively.2 Until recently, very little has been known about the cellular roles of PPAR, even though it is by far the most ubiquitously expressed of the PPAR receptors.1,3 The recent development of highly selective ligands and PPARβ/ knockout and transgenic mice, however, have now implicated roles for PPARβ/ in adipose tissue formation, metabolism, wound healing, brain development, placental function, colorectal carcinogenesis, and skeletal muscle function.4–6 PPARβ/ ligands appear highly effective in regulating lipid metabolism, particularly in skeletal muscle,7,8 and are currently in phase II clinical trials for treatment of dyslipidemia, aimed particularly at individuals with low HDL levels.
All of the PPARs, therefore, appear to be able to target aspects of the metabolic syndrome.6 Because the metabolic syndrome represents a major risk factor for cardiovascular diseases, there has been an increasing interest in the roles of PPARs, in particular most recently PPARβ/, in vascular biology. Indeed, in addition to the treatment of dyslipidemia, PPARβ/ ligands may reduce the development in atherosclerosis in the high-fat Western diet LDL receptor–/– mouse model.9,10 A similar study using adoptive transfer of PPARβ/–/– monocytes in to LDL receptor–/– mice11 revealed that at the molecular level, PPARβ/ acts as a switch to control monocyte inflammation via a ligand-dependant interaction with the transcriptional repressor BCL-6. In the unliganded state, PPARβ/ binds BCL-6. On activation with PPARβ/ ligand, BCL-6 is released and is free to suppress pro-inflammatory pathways which lead to inflammatory atherosclerosis and foam cell formation.11 Counterintuitively, a similar result to PPARβ/ activation is also found in cells, where PPARβ/ protein has been suppressed by small interfering RNA or knocked out altogether, because there is no longer any endogenous PPARβ/ available to bind and inhibit the actions of BCL-6.
Over the last year, there has been an increased interest in the direct roles of PPARβ/ in vascular cells. Indeed, this PPARβ/–BCL-6 interaction, originally described in monocytes, has similarly been shown in vascular endothelial cells to regulate the inhibition of tumor necrosis factor –induced adhesion molecule expression.12,13 Moreover, independently, PPARβ/ appears to play an important role in inducing endothelial cell angiogenesis14–16 and the development of tumor vasculature.15,16 In contrast, the roles and actions of PPARβ/ in vascular smooth muscle, however, have remained relatively elusive.
In this issue of Circulation Research, Kim et al17 show that PPARβ/ inhibits vascular smooth muscle inflammation and proliferation through the induction of transforming growth factor (TGF)β1. The TGFβ family consists of 3 family members: TGFβ1, -β2, and -β3. TGFβ1 is an established antiinflammatory/profibrosis target in the vasculature, with its targeted disruption leading to the promotion of atherosclerosis and in particular unstable atherosclerotic plaque development attributable to a change in the balance of inflammation and fibrosis.18–20 Using rat and human vascular smooth muscle cells, the authors show that activation of PPARβ/ but not PPAR or PPAR induces TGFβ1 at the transcriptional level via the presence of a classic PPAR response element, which the PPARβ/–retinoid X receptor heterodimer binds and activates. Downstream of TGFβ1, the antithrombotic target plasminogen activator inhibitor-1 is induced, smooth muscle cell proliferation is inhibited, and the levels of the proinflammatory chemokine monocyte chemoattractant protein-1 are reduced (Figure). All of these "protective" vascular effects of PPARβ/ ligand activation can be shown to be mediated, at least in part, via TGFβ1 activation of its receptor, which downstream may involve the activation of its intracellular effecter smad3 (Figure).
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PPARβ/, like PPAR and PPAR, is clearly active and expressed in vascular and inflammatory cells. PPARβ/ ligands potently reduce vascular inflammation via at least 2 different pathways: the release of the transcriptional repressor BCL-6 and via the induction of TGFβ1. Work now needs to show whether these promising findings translate into a therapeutic advance in humans whereby PPARβ/ ligands can be used to limit both the dyslipidemia and directly vascular disease progression.
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Acknowledgments |
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Sources of Funding
D.B.-B. is funded by grants from the Barts and the London Research Advisory Board and European Union 6th Framework Programme grant LSHM-CT-2004-0050333.
Disclosures
None.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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References |
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