doi: 10.1161/01.RES.0000151331.69399.b2
© 2004 American Heart Association, Inc.
Editorials |
Oxidative Stress and Peroxisome Proliferator–Activated Receptors
Reversing the Curse?
From the Donald W. Reynolds Cardiovascular Clinical Research Center, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Dr Jorge Plutzky, Brigham and Women’s Hospital, 77 Ave Louis Pasteur, NRB740, Boston, MA 02115. E-mail jplutzky{at}rics.bwh.harvard.edu
See related article, pages 1174–1182
Key Words: PPARs • oxidation • LDL • NADPH • inflammation
The most common view of lipoproteins focuses on their role in lipid transport.1 By making lipids miscible in plasma, lipoproteins deliver triglycerides, and their incorporated fatty acids, to muscle for energy use or to adipose tissue for storage, the latter seeming all too often the case. Likewise, lipoprotein transport provides cholesterol to cells for essential functions like membrane formation and steroid hormone synthesis. More recent work has expanded this perspective, revealing how lipoproteins can help deliver specific signals to the nucleus of cells, inducing targeted transcriptional responses in tissues far removed from where the lipoprotein particle originated. Indeed, extensive data now identify lipid signaling to the nucleus in many key biological pathways, including cellular determination, cell differentiation, and adaptive homeostasis.2
One process in which lipoproteins and bioactive lipid metabolites have been strongly implicated is inflammation, including both its initiation and resolution.2 In this regard, peroxisome proliferator–activated receptors, or PPARs, have received considerable attention as a mechanism for transducing such lipid signals into transcriptional responses.3 PPARs, members of the steroid hormone receptor family, help regulate the expression of key genes involved in lipid metabolism, adipogenesis, and glucose control; more recent evidence suggests a role for PPARs in inflammation and atherosclerosis as well.4 The three PPAR isoforms (PPAR-
, PPAR-ß, PPAR-
) share many attributes while maintaining distinct features, including differences in expression patterns, cognate ligands, coactivator/corepressor interactions, target genes, and species differences, with the latter including peroxisomal proliferation itself.5 Despite this daunting complexity, the ongoing clinical use of synthetic PPAR agonists in humans, like PPAR-–activating fibrates to lower lipid levels and PPAR-–activating thiazolidinediones to treat diabetes, establishes the translational relevance of this field. This established and emerging body of PPAR data also underscore the importance of understanding PPAR activation in vivo—not through xenobiotics but rather through naturally occurring PPAR agonists—and how PPAR activation under endogenous conditions determines cellular responses.6
In this issue of Circulation Research, Teissier et al extend our insight into the connections between PPARs, LDL metabolism, and oxidative stress.7 The oxidized form of LDL (ox-LDL) promotes inflammation in part via ox-LDL uptake by scavenger receptors and subsequent nuclear factor 
B activation.8 Teissier et al find that synthetic PPAR agonists induce the production of reactive oxygen species (ROS) in a PPAR-–dependent manner by inducing NADPH oxidase, a key enzyme in oxidative stress.9 Moreover, these investigators offer the intriguing notion that ROS interact with LDL to activate PPAR- and subsequently limit inflammation, as indicated by PPAR-dependent repression of inducible nitric oxide synthase (iNOS) gene transcription.
As with any valuable study, these findings foster numerous important questions. What are the specific PPAR- activators generated by ROS/LDL interaction? What is the PPAR-–dependent molecular mechanism accounting for the inhibition of lipopolysaccharide-induced iNOS transcription? Further work is needed to answer these issues; as a result, we may also better understand the functional significance of PPAR responses to oxidative stress through NADPH oxidase. Separately, it will be of interest to ask how these responses in macrophages apply to other cellular settings. Important distinctions exist between NADPH oxidases in macrophages, as studied by Teissier et al, and vascular cells like endothelial cells and vascular smooth muscle cells, where NADPH oxidase is more clearly involved in promoting atherosclerosis.9 The fact that these vascular cells also express PPAR- raises obvious questions as to the coordinated regulation of inflammation and the physiological versus pathological balance of these pathways in the arterial wall.6
Future studies that address these issues may also help resolve larger questions regarding the molecular and cellular mechanisms in the dynamics of inflammation. How are naturally occurring inflammatory lipid/lipoprotein stimuli, like ox-LDL and eicosanoids, produced and their responses coordinated and regulated? Are the signals that direct inflammation generated intracellularly (autocrine; Figure, B), from neighboring cells (paracrine; Figure, A), or transported from other organs via the bloodstream (endocrine; Figure, C)? Likewise, do autocrine, paracrine, or endocrine pathways also help limit and/or terminate inflammation? Our current maps of these molecular events remain crude given the reductionist approaches required to study such complex events. Nevertheless, the data from Teissier et al suggest one possible paracrine signaling pathway whereby PPAR-, in response to ox-LDL, may limit at least one model inflammatory response, iNOS production (Figure, A). How these results overlay on the complexity of PPAR biology noted earlier—other PPAR isoforms, other inflammatory target genes, and applicability to human biology—remains to be determined.
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These findings add to other reports of lipoproteins/lipid molecules as natural PPAR agonists, including the role of such mediators in inflammation and its resolution. Early seminal work revealed that distinct fatty acids could bind to and activate all PPAR isoforms, at least in vitro.10,11 Oxidation modification of certain fatty acids can limit leukocyte adhesion in vivo in a PPAR-–dependent manner.12 Leukotriene B4, a proinflammatory lipid mediator, can activate PPAR-,13 initiating a cascade for terminating inflammation in an autocrine fashion (Figure, B). Lysophosphatidic acid, a component found in LDL, has been reported as a natural PPAR- agonist.14 Recently, our group15 as well as that of Evans16 identified a common pathway of triglyceride metabolism, namely the action of lipoprotein lipase (LPL) on triglyceride-rich lipoproteins, as a mechanism for PPAR activation. Like synthetic PPAR- agonists, LPL hydrolysis of triglyceride-rich lipoproteins repressed cytokine-induced adhesion molecule expression, but only in wild-type and not PPAR-deficient endothelial cells.15,17 These data suggest a possible endocrine-like mechanism for limiting inflammation through LPL-mediated PPAR responses (Figure, C). Subsequent studies revealed that LPL can act on electronegative LDL, a LDL species with potent proinflammatory effects in vitro, to release a known PPAR- and PPAR- agonist (hydroxyoctadecadienoic acids).16 LPL treatment completely reversed the proinflammatory effects of electronegative LDL on endothelial adhesion molecule expression in a PPAR-–dependent manner. These data are quite synergistic with the findings from Tessier et al7: the inflammatory response to different LDL species appears determined by the metabolism of the lipoprotein, the generation of distal PPAR- metabolites, and the coordinated, if still incompletely understood, cellular response.
Even while a better understanding of how lipoprotein/lipid-induced transcription regulates inflammation is pursued, the data from Teissier et al serve as an example of how the difference between physiological responses and pathological consequences may rest in the balance of a given pathway. Oxidation, oxidative stress, or even ROS production are not necessarily pathogenic. For example, the ß-oxidation of fatty acids, a pathway largely regulated by PPAR-, is critical to energy utilization. Likewise, ROS production is important for growth factor responses, cell signaling, and the bactericidal function of macrophages.18 In this sense, the ability to generate energy through oxidation, or destroy bacteria through ROS generation, might be seen as a biological blessing. In contrast, extensive data suggest these same pathways, through ROS or ox-LDL, when dysregulated or excessive, appear to be something of a curse, contributing to major pathological conditions like atherosclerosis. The emerging network of lipid signaling to the nucleus, and perhaps particularly to PPARs, through endocrine, autocrine, and paracrine responses, may be one way in which inflammatory responses are reversed before a pathological curse can be uttered.
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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Related Article:
Induces NADPH Oxidase Activity in Macrophages, Leading to the Generation of LDL with PPAR- Activation Properties
Circ. Res. 2004 95: 1174-1182.
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