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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:628.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Tetradecylselenoacetic Acid, a PPAR Ligand With Antioxidant, Antiinflammatory, and Hypolipidemic Properties

Endre Dyrøy; Therese H. Røst; Reidar J. Pettersen; Bente Halvorsen; Oddrun A. Gudbrandsen; Thor Ueland; Ziad Muna; Fredrik Müller; Jan E. Nordrehaug; Pål Aukrust; Rolf K. Berge

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

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