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Originally published In Press as doi:10.1074/jbc.M204639200 on October 3, 2002

J. Biol. Chem., Vol. 277, Issue 51, 49319-49325, December 20, 2002
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Branched Chain Fatty Acids Induce Nitric Oxide-dependent Apoptosis in Vascular Smooth Muscle Cells*

Susanne IdelDagger §, Peter EllinghausDagger , Christian Wolfrum§||, Jerzy-Roch NoferDagger **, Jolein GloerichDagger Dagger , Gerd AssmannDagger **, Friedrich Spener§, and Udo SeedorfDagger **§§

From the Dagger  Institute for Arteriosclerosis Research, the § Department of Biochemistry, and the ** Institute for Clinical Chemistry and Laboratory Medicine, Central Laboratory, University of Münster, 48129 Münster, Germany and the Dagger Dagger  Institute of Biomembranes and Biochemistry of Lipids, University of Utrecht, 3584 CH Utrecht, The Netherlands

Clinical observations in patients with peroxisomal disorders and studies employing corresponding mouse models have shown that supraphysiological concentrations of dietary branched chain fatty acids (BCFAs) are associated with a high level of toxicity, which is poorly understood at present. Here we show that phytanic and pristanic acid, two BCFAs that are metabolized in peroxisomes, promote apoptosis in cultured vascular smooth muscle cells of human, rat, and porcine origin. Under the conditions used, the apoptosis-promoting effect of BCFAs was neither shared by saturated or unsaturated straight chain fatty acids nor by artificial peroxisome proliferators, which, like phytanic and pristanic acid, have been shown to activate the peroxisome proliferator-activated receptor alpha  (PPARalpha ). We could demonstrate, however, that BCFA induced tumor necrosis factor alpha  (TNFalpha ) activation and secretion, which is an obligatory step required for induction of apoptosis by BCFAs. Furthermore, incubation of VSMCs with BCFA increased inducible nitric-oxide synthase (iNOS) mRNA and protein concentrations markedly within 2 h of treatment. Correspondingly, apoptosis was significantly reduced when the cells were co-treated with the competitive NOS inhibitors monomethyl-L-arginine monoacetate and aminoguanidine. Moreover, co-incubation with TGFbeta 1, previously shown to destabilize iNOS mRNA, also abolished apoptosis. These results establish a new signaling cascade in which natural BCFA induced NO-dependent apoptosis, which is apparently triggered by autocrine secretion of TNFalpha in cultured VSMCs.

* This work was supported by Grants Se 459/2-3 and Sp 135/12-1 provided by the Land Nordrhein-Westfalen, the Deutsche Forschungsgemeinschaft, and the Interdisziplinäres Zentrum für Klinische Forschung, IZKF of the Medical faculty, University of Münster (Project A4).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Bayer AG, Dept. of Cardiovascular Research, 42096 Wuppertal, Germany.

|| Present address: Rockefeller University, Dept. of Genetics of Metabolic Diseases, New York, NY 10021.

§§ To whom correspondence should be addressed: Inst. for Arteriosclerosis Research, Domagkstr. 3, 48149 Münster, Germany. Tel.: 49-251-8356197; Fax: 49-251-8355187; E-mail: seedorfu@uni-muenster.de.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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