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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1364.)
© 2005 American Heart Association, Inc.

Vascular Biology

Antiinflammatory Effects of Tetradecylthioacetic Acid Involve Both Peroxisome Proliferator–Activated Receptor –Dependent and –Independent Pathways

Endre Dyrøy; Arne Yndestad; Thor Ueland; Bente Halvorsen; Jan Kristian Damås; Pål Aukrust; Rolf K. Berge

From the Institute of Medicine (E.D., R.K.B.), Section of Medical Biochemistry, University of Bergen, Haukeland University Hospital, Bergen; and the Research Institute for Internal Medicine (A.Y., T.U., B.H., J.K.D., P.A.), Section of Endocrinology (T.U.), and Section of Clinical Immunology and Infectious Diseases (P.A.), Medical Department, Rikshospitalet, University of Oslo, Oslo, Norway.

Correspondence to Endre Dyrøy, Section of Medical Biochemistry, Institute of Medicine University of Bergen, Haukeland University Hospital N-5021, Bergen, Norway. E-mail endre.dyroy{at}med.uib.no

Objective— Tetradecylthioacetic acid (TTA) is a hypolipidemic antioxidant with immunomodulating properties involving activation of peroxisome proliferator–activated receptors (PPARs). Human endothelial cells express PPARs. We hypothesized that TTA could modulate endothelial cell activation at least partly through PPAR-related mechanisms.

Methods and Results— We explored this hypothesis by different experimental approaches involving both in vitro studies in human endothelial cells (HUVECs) and in vivo studies in humans and PPAR-^–/– mice. Our main findings were as follows: (1) TTA suppressed the tumor necrosis factor –induced expression of vascular cell adhesion molecule 1 (VCAM-1) and interleukin 8 (IL-8) in HUVECs. (2) No TTA-mediated attenuation of VCAM-1 and chemokine expression was seen in the liver of PPAR-^–/– mice. (3) Whereas TTA markedly enhanced PPAR-–target genes in the liver of wild-type, but not of PPAR-^–/–, mice, no such effect on PPAR-–target genes was seen in HUVECs. (4) The relevance of our findings to human disease was suggested by a TTA-mediated downregulation of serum levels of soluble VCAM-1 and IL-8 in psoriasis patients.

Conclusion— We show that TTA has the ability to attenuate tumor necrosis factor –mediated endothelial cell activation, further supporting antiinflammatory effects of this fatty acid, possibly involving both PPAR-–dependent and –independent pathways.

We show that tetradecylthioacetic acid attenuates tumor necrosis factor-–mediated endothelial cell activation, supporting antiinflammatory effects of this fatty acid. The relevance of our findings to human diseases was suggested by a tetradecylthioacetic acid–mediated downregulation of inflammatory mediators in psoriasis patients.

Key Words: endothelial dysfunction • inflammation • cytokine • peroxisome proliferator–activated receptors

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