Published online before print December 21, 2006, doi: 10.1161/01.ATV.0000255950.70774.d5
© 2007 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Tetradecylselenoacetic Acid, a PPAR Ligand With Antioxidant, Antiinflammatory, and Hypolipidemic Properties
From the Institute of Medicine, Section of Medical Biochemistry (E.D., T.H.R., O.A.G., Z.M., R.K.B.), University of Bergen; Departments of Medicine (T.H.R.) and Heart Disease (R.J.P., J.E.N.), Haukeland University Hospital, Bergen; Research Institute for Internal Medicine (B.H., T.U., F.M., P.A.), Section of Endocrinology (T.U.), Medical Department, Institute of Medical Microbiology (F.M.), Rikshospitalet University Hospital, University of Oslo, Norway.
Correspondence to Rolf Kristian Berge, Institute of Medicine, Section of Medical Biochemistry, Haukeland University Hospital, N-5021 Bergen, Norway. E-mail rolf.berge{at}med.uib.no
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Abstract |
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Objective— Antioxidants protect against oxidative stress and inflammation, which, in combination with hyperlipidemia, are important mediators of atherogenesis. Here we present a selenium-substituted fatty acid, tetradecylselenoacetic acid (TSA), which is hypothesized to have antioxidant, antiinflammatory, and hypolipidemic properties.
Methods and Results— We show that TSA exerts antioxidant properties by delaying the onset of oxidation of human low density lipoprotein (LDL), by reducing the uptake of oxidized LDL in murine macrophages, and by increasing the mRNA level of superoxide dismutase in rat liver. TSA also showed antiinflammatory effects by suppressing the release of interleukin (IL)-2 and -4, and by increasing the release of IL-10 in human blood leukocytes. In addition, TSA decreased the plasma triacylglycerol level and increased the mitochondrial fatty acid ß-oxidation in rat liver. In pigs, TSA seemed to reduce coronary artery intimal thickening after percutaneous coronary intervention. In HepG2 cells TSA activated all peroxisome proliferator-activated receptors (PPARs) in a dose-dependent manner.
Conclusions— Our data suggest that TSA exert potent antioxidant, antiinflammatory, and hypolipidemic properties, potentially involving PPAR-related mechanisms. Based on these effects, it is tempting to hypothesize that TSA could be an interesting antiatherogenic approach to atherosclerotic disorders.
We explored the antioxidant, antiinflammatory, and hypolipidemic effects of TSA, a selenium-substituted fatty acid. Through mechanisms that seem to involve PPAR activation, TSA protects LDL from oxidation, has antiinflammatory effects in human leukocyte, and has lipid lowering properties in rat liver and plasma.
Key Words: 3-seleno fatty acid • LDL oxidation • antiinflammatory • PPAR activation • antiatherogenic
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Introduction |
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Atherosclerosis is regarded as an inflammatory disorder of the vascular wall, where multiple factors contribute to a persistent and self-perpetual inflammation within the atherosclerotic lesions.1–5 There is also a consensus that atherosclerosis represents a state of elevated oxidative stress characterized by lipid and protein oxidation in the vascular wall.6 Enhanced inflammation and oxidative stress seem to represent a vicious circle in atherogenesis, and therapeutic options directed against these processes seems like a reasonable approach in the management of atherosclerotic disorders.
We have previously shown that tetradecylthioacetic acid (TTA), a modified fatty acid with a sulfur atom in the third position of the carbon backbone, promotes mitochondrial and peroxisomal proliferation, and decreases serum lipid levels in animal models.7–9 TTA also shows antioxidant effects in vitro10 and encompasses antiinflammatory properties in human leukocytes.11 The pleiotropic effects of TTA seem to involve activation of peroxisome proliferator-activated receptors (PPARs),12,13 which are receptors that serves as an important link between lipid metabolism and inflammation.14–17
Tetradecylselenoacetic acid (TSA) is a novel fatty acid which in comparison to TTA has a selenium atom instead of a sulfur atom in third position of the carbon backbone. As with TTA,18 this modification makes TSA resistant to fatty acid ß-oxidation. A previous in vitro study has demonstrated that TSA is a stronger antioxidant than TTA.19 Based on these findings and its relation to TTA, we hypothesized that TSA also exerts potent antiinflammatory and hypolipidemic effects, potentially involving PPAR-related mechanisms.
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Materials and Methods |
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A complete online Method section is available in the online data supplement at http://atvb.ahajournals.org.
Assessment of Low Density Lipoprotein Oxidation
Low density lipoprotein (LDL) was isolated from human plasma10,20 and oxidized by Cu2+-ions or azo-compounds that decompose to peroxyl radicals. Formation of conjugated dienes was monitored as previously described.10 The electrophoretic mobility was assayed by agarose gel electrophoresis and lipid peroxides were measured as absorbance at 675 nm.
Uptake of Oxidized and Native 125I-TC-LDL in Macrophages and Fibroblasts
Isolated LDL was radiolabeled with 125I-tyraminylcellobiose (TC; 125I-TC-LDL)21 and oxidized in a cell-free system in the presence of ethanol (control), PA, or TSA. Cellular uptake of oxidized/native 125I-TC-LDL to murine J774 A1 macrophages (J774) and human skin fibroblasts (HSF) was measured as cell-associated radioactivity (cpm/mg cell protein).22
TSA Treatment of Wistar Rats
TSA, synthesized as previously described,19 was administered daily to male Wistar rats (Mol:Wist) from Møllegard Breeding Laboratorium (Ejby, Denmark) by orogastric intubation (8, 15,* or 25 mgKg–1day–1 for 4 days; *also for 8 days). The protocol was approved by the Norwegian State Board of Biological Experiments with Living Animals.
RNA Isolation and Northern Blot Analysis
Total RNA was extracted from rat liver by the acid guanidium thiocyanate-phenol-chloroform method.23 The RNA was run on a gel, Northern blotted, and quantified by PhosphoImager STORM 860 (Molecular Dynamics).24
Enzyme Immunoassays
Concentration of cytokines in peripheral blood mononuclear cell (PBMC) supernatants were analyzed by enzyme immunoassays using kits for interleukin (IL)-10 (CLB), IL-2 (R&D Systems), IL-4 (R&D Systems), interferon (IFN)-
(Biosource International) and tumor necrosis factor (TNF)-
(Biosource International).
Preparation of Liver Homogenates, Subcellular Fractions, and Enzyme Activities
Rat liver homogenates were prepared.25 Total palmitoyl-coenzyme A (CoA) oxidation and palmitoyl-L-carnitine oxidation were measured in mitochondrial fraction.26 Fatty acyl-CoA oxidase (ACO) activity was measured in peroxisomal fraction.27
Fatty Acid Composition
Rat liver and plasma lipids were extracted28 and analyzed as previously described.29,30 The antiinflammatory fatty acid index [(C20:3n-6 + C22:5n-3 + C22:6n-3)/C20:4n-6] was calculated as described elsewhere.31
Plasma Lipid Measurements
Plasma lipids were measured enzymatically on a Technicon Axon system (Miles).
PPAR Luciferase Activity
HepG2 cells were transiently transfected (0.90 µg PPREx3-LUC, 0.15 µg pcDNA3.1 hPPAR/
/, 0.95 µg pCMV-5) using SuperFect (Qiagen), and treated with specific PPAR agonists or TSA for 24 hours. Luciferase activity was measured on a LUCY-1 luminometer (Anthos).
RNA Isolation and Real Time RT-PCR
Total RNA was purified from HepG2 cells using RNeasy Mini Kit (Qiagen). Real-time RT-PCR was carried out on an ABI7900 sequence detection system (Applied Biosystems) using primers and TaqMan probes.
Vessel-Injury in Pigs
The coronary artery of healthy domestic pigs (
40 kg) was injured and TSA (6 mmol/L in 16% BSA) was administered at the site of injury. Cryostat sections of the coronary arteries were prepared for hematoxylin and eosin staining (HE-staining). The protocol was approved by the Norwegian State Board of Biological Experiments with Living Animals.
Statistical Analysis
Results are presented as mean±SD. The data were evaluated by two-tailed Student t test, with the level of statistical significance at P<0.05.
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Results |
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LDL Oxidation by Cu2+ and Azo-Compounds
Human LDL particles were isolated and Cu2+-induced oxidation performed in a cell-free system. Whereas the lag time before onset of Cu2+-induced oxidation was only marginally affected after PA treatment (supplemental Figure IA), TSA significantly increased the lag time and the half-time (supplemental Figure IA-B) in a dose-dependent manner. After Cu2+-induced oxidation we also observed a delayed shift in the electrophoretic mobility of isolated LDL incubated with TSA (supplemental Figure IC). Furthermore, the level of lipid peroxides after oxidation by lipid-soluble 2,2'-azobis-(2,4-dimethylvaleronitrile) (AMVN) and water-soluble 2,2'-azobis-(2-aminopropane hydrochloride) (AAPH) azo-compounds was decreased after TSA treatment (supplemental Figure ID). Altogether these results suggest that TSA at concentrations lower than 10 µmol/L exert antioxidant effects on LDL oxidation induced by Cu2+, AMVN and AAPH.
Cellular Uptake of Native/Oxidized LDL to Macrophages and Fibroblasts
Because J774 macrophages mainly express scavenger receptors for oxidized LDL, and HSF fibroblasts mainly express LDL receptor for native LDL, the uptake of oxidized/native radiolabeled 125I-TC-LDL in these cells will reflect the degree of LDL oxidation. Before addition to the cell cultures, 125I-TC-LDL was oxidized in a cell-free system for 0 to 24 hours in the presence of ethanol (control), PA, or TSA. In J774 macrophages the uptake of 125I-TC-LDL that was oxidized in the presence of TSA was decreased after 10 hours oxidation (Figure 1A), and after 24 hours the difference was more pronounced (Figure 1A). In HSF cells the uptake of native 125I-TC-LDL was higher in TSA-treated fractions, as compared with control and PA, particularly after 10 and 24 hours oxidation (Figure 1B). These data suggest that TSA protects 125I-TC-LDL against Cu2+-induced oxidation, and thereby render more native 125I-TC-LDL available for uptake in HSF cells (Figure 1B).
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Superoxide Dismutase
In rats TSA significantly increased the hepatic mRNA levels of Mn-superoxide dismutase (MnSOD) and CuZnSOD (Figure 2), which protects against enhanced superoxide anion production, further supporting the role of TSA as an antioxidant.
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Release of Cytokines in PBMCs
To investigate whether the antioxidant effects of TSA were accompanied by antiinflammatory properties, we examined the release of cytokines in PBMCs. Although TSA had no effect on cytokine release in unstimulated cells (data not shown), it significantly downregulated the release of IL-2 and IL-4 (Figure 3A and 3B), but not the release of TNF- or IFN- (data not shown), in phytohemagglutinin (PHA)-stimulated PBMCs. TSA also markedly enhanced the release of IL-10 in PBMCs after stimulation with PHA, lipopolysaccharide (LPS), or TNF- (Figure 3C).
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TSA was given as a complex with BSA, which is acknowledged to reduce the cellular uptake, and hence the toxicity.32 Propidium iodide staining, followed by flow cytometry, showed a very modest increase in nonviable cells (<8%) during TSA exposure (data not shown). Although we lack data on IL-4 release in PHA-stimulated cells and on IL-10 release in LPS stimulated cells on lower TSA concentrations, 25 µmol/L TSA was also demonstrated to decrease IL-2 release in PHA-stimulated cells and to increase IL-10 release in PHA and TNF- stimulated cells (data not shown).
Fatty Acid Metabolism in Rat Liver
Rats were treated with TSA for 4 to 8 days, and TSA was recovered in both liver and plasma. No chain-shortened metabolites of TSA was found, supporting that as with the sulfur atom in TTA,18 the position of the selenium atom in TSA makes it resistant to ß-oxidation. TSA did however affect the metabolism of natural fatty acids in rat liver, as the mitochondrial palmitoyl-L-carnitine (Figure 4A) and palmitoyl-CoA (supplemental Figure IIA) oxidation was increased. Also, the mRNA level (Figure 4B) and the activity of ACO (supplemental Figure IIB) as well as the mRNA levels of carnitine palmitoyltransferase (CPT)-I (Figure 4C) and CPT-II (supplemental Figure IIC), were significantly increased in TSA-treated rats. Because TSA increased the fatty acid ß-oxidation, the fatty acid composition may also be affected. TSA treatment decreased the amount of C18:0 in the rat liver (Table). This was accompanied by increased levels of monounsaturated fatty acids, C18:1n-9 in particular, indicating increased 
9 desaturase activity. TSA also increased the level of C18:3n-6 and C18:3n-3, and decreased the level of C20:3n-6 and C20:5n-3. The significant increase in the 5 (C20:4n-6/C20:3n-6) and the 6 (C18:3n-6/C18:2n-6) desaturase indexes (Table) suggested that TSA also may enhance the 5 and 6 desaturase activities. The total level of n-3 and n-6 polyunsaturated fatty acids, and the n-3/n-6 ratio was unchanged in liver after TSA administration (Table).
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Plasma Fatty Acids and Lipids
In plasma of TSA-treated rats the amount of C18:0 was decreased, whereas C18:3n-6 was increased (Table). The total amount of n-3 fatty acids was also increased in plasma after TSA treatment. This was mostly attributed to an increase in C22:6n-3 (Table), which also contributed to a significant increase in the antiinflammatory fatty acid index (control 0.43±0.07; TSA 0.64±0.10; P<0.05). Administration of 15 mg TSA for 8 days also lowered triacylglycerol, cholesterol, and phospholipids levels in plasma (Figure 4D and 4E; supplemental Figure IID).
PPAR Dependent Transcriptional Activity and mRNA Level of PPAR Target Genes
On the basis of the role of PPARs in TTA-mediated effects, we examined the ability of TSA to activate PPAR// in transiently transfected HepG2 cells. Specific PPAR ligands were used as positive controls for comparison. WY14.643 was used as a specific PPAR ligand, whereas L165.041 and BRL49653 were used as specific PPAR and PPAR ligands, respectively. TSA activated all PPARs in a dose-dependent manner (Figure 5), with more pronounced effect on PPAR and PPAR. In agreement with the increased mRNA levels of the PPAR target genes, ACO, CPT-I, and CPT-II in the liver of TSA-treated rats (Figure 4B and 4C; supplemental Figure IIC), the gene expression of the PPAR target genes, fatty acid translocase (CD36), and ACO, was also significantly increased in TSA-treated HepG2 cells (supplemental Figure III).
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Intimal Thickening After Percutaneous Coronary Intervention
Although restenosis after percutaneous coronary intervention (PCI) is different from atherosclerosis, these processes share some of the same characteristics, such as smooth muscle cell proliferation and intimal matrix formation induced by arterial wall injury, as well as a wound-healing response to severe intimal and medial damage, involving enhanced inflammation and oxidative stress. We therefore examined the effect of TSA on coronary arteries after PCI in pigs. As shown in supplemental Figure IV, smooth muscle cell proliferation and intimal thickening after PCI seemed to be prevented after TSA treatment as compared with control.
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Discussion |
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In this study we show for the first time that TSA, in addition to its antioxidant properties,19 exert potent antiinflammatory and hypolipidemic effects. Although the in vitro data from these experiments cannot be translated directly to the in vivo situation, the TSA concentration used in most of the in vitro experiments was in a similar range as the plasma concentration of TSA in vivo (15 to 45 µmol/L; 15 mgKg–1day–1 TSA, 4 to 8 days), supporting the in vivo relevance of our findings.
We demonstrate the antioxidant properties of TSA by different experimental setups. TSA prolonged the lag phase before the onset of Cu2+-induced LDL oxidation. TSA also seemed to protect the protein moiety of the LDL particle against oxidation, as observed by delayed shift in the electrophoretic mobility of LDL. In addition, TSA reduced the oxidation of LDL after Cu2+-exposure, assessed as decreased uptake of oxidized 125I-TC-LDL in J774 macrophages and increased uptake of native 125I-TC-LDL in HSF. The fact that TSA also was effective in reducing the level of lipid peroxides after azo-compound induced LDL oxidation indicates a radical scavenging rather than a Cu2+-ion binding effect. TSA also increased the gene expression of the antioxidant enzymes MnSOD and CuZnSOD in the liver of TSA-treated rats, suggesting that the antioxidant effects of TSA also may be operating in vivo. In regard to oxidative events in atherosclerosis, azo-compounds, which decompose to peroxyl radicals, might be more relevant than Cu2+ induced oxidative stress,6 and forthcoming studies should examine the in vivo relevance of TSA as an antioxidant in relation to oxidative stress in atherosclerotic disorders.
This study demonstrates for the first time that TSA has immunomodulating properties. Whereas TSA decreased the release of IL-4 and particularly of IL-2 in activated PBMCs, it markedly enhanced the release of the antiinflammatory cytokine IL-10. These effects could potentially be secondary to the antioxidant properties of TSA, but the lack of effect on TNF- suggest that other mechanisms, possibly involving PPARs,14–17 may be operating. The ability of TSA to enhance IL-10, particularly in response to TNF-, may be of interest from a therapeutic point of view in disorders where TNF- play a pathogenic role, such as atherosclerosis.33 We have previously reported that the sulfur-substituted fatty acid, TTA, also possesses antiinflammatory properties in activated PBMCs.11 However, TSA seems to suppress IL-2 and IL-4 release and enhance IL-10 release to a greater extent than TTA. Although IL-4 is regarded as a Th2-derived cytokine, it exhibit inflammatory and oxidative properties,34 and has been suggested to contribute to vascular inflammation in disorders such as atherosclerosis and asthma.34,35
We demonstrate the lipid lowering effect of TSA by decreased plasma levels of triacylglycerol, phospholipids, and cholesterol in rats. This could be explained by enhanced mitochondrial and peroxisomal ß-oxidation observed after TSA treatment. The hypolipidemic effect was accompanied by changes in fatty acid composition in liver, indicating enhanced 5 and 6 desaturase activity. Moreover, TSA increased the antiinflammatory fatty acid index in plasma, supporting its antiinflammatory properties. Interestingly, in a transgenic hTNF- mouse model, which resembles chronic inflammation, the gene expression of 9 desaturase was decreased.36 Thus, the increased amount of 18:1n-9 after TSA may contribute to its antiinflammatory effects.
There is a high rate of restenosis after PCI,37 a process that shares some of the same characteristics as atherosclerosis, involving both inflammation and oxidative stress.37 We have previously shown that TTA reduces restenosis in pigs.37 Selenium is a stronger reducing agent than sulfur, and our data indicate that TSA may reduce the degree of coronary artery intimal thickening in pigs undergoing PCI. These findings suggest that the antioxidant, antiinflammatory, and hypolipidemic properties of TSA may not merely be an in vitro phenomenon, but could induce antiproliferative effects after PCI in vivo.
We have previously demonstrated that the pleiotropic effects of TTA may involve all PPAR subtypes.12,13 Here we show that TSA may activate all PPAR subtypes in a dose-dependent manner in transiently transfected HepG2 cells. Moreover, in rats receiving TSA, the hepatic mRNA levels of the PPAR target genes ACO, CPT-I, and CPT-II were significantly increased. TSA also significantly increased the mRNA levels of the PPAR target genes ACO and CD36 in HepG2 cells. The increase in these PPAR target genes may suggest PPAR activation, but recent studies suggest that also other PPARs may be involved in the regulation of these genes.38 CD36 is reported to be regulated by PPAR and PPAR in liver and adipose tissue, respectively,39,40 and by PPAR in macrophages41 and skeletal muscle,42 underscoring the complexity of the PPAR system in which the responses to a certain ligand may differ between different cell types and tissues. Several studies have suggested antiinflammatory effects after PPAR14,15 and PPAR activation,16 although the antiinflammatory properties of PPAR are more controversial. Recently, an important role of PPAR in inflammation has also been reported.17 Thus, based on the data from the HepG2 and rat liver experiments, it is tempting to hypothesize that the antiinflammatory effects of TSA in PBMCs may involve pan-PPAR activation. Nevertheless, although the relative importance of the various PPARs in the TSA mediated effects is not clear, our findings strongly suggest that activation of PPARs could be involved.
In summary, our data suggest that TSA has potent antioxidant, antiinflammatory, and hypolipidemic effects, possibly involving PPAR-related mechanisms. Whether these properties will result in antiatherogenic effects in vivo will have to be investigated in forthcoming studies using animal models of atherosclerotic disorders.
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Acknowledgments |
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We thank Svein Krüger, Kari Williams, Liv Kristine Øysæd, Randi Solheim, Randi Sandvik, and Terje Ertkjern for technical assistance, and the Medical Research Centre, University of Bergen, for providing technical equipment.
Sources of Funding
This work was financially supported by the Norwegian Council on Cardiovascular Disease, the Western Norway Regional Health Authority, the Norwegian Cancer Society, the Norwegian Association of Heart and Lung Patients, the Novo Nordic Foundation, and the University of Bergen.
Disclosures
Thia Medica AS holds patents regarding effects of TSA. Jan E. Nordrehaug and Rolf K. Berge, as well as the University of Bergen, are shareholders of Thia Medica AS. There are no conflicts of interest.
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Footnotes |
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E.D. and T.H.R. contributed equally to this study.
Original received September 12, 2006; final version accepted November 30, 2006.
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