Branched chain fatty acids induce nitric oxide-dependent apoptosis in vascular smooth muscle cells.

Abstract

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 TGFbeta1, 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.

• Authors: Susanne Idel, Peter Ellinghaus, Christian Wolfrum, Jerzy-Roch Nofer, Jolein Gloerich, Gerd Assmann, Friedrich Spener, Udo Seedorf
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 277 Issue 51 Pg. 49319-25 (Dec 20 2002) ISSN: 0021-9258 [Print] United States
• PMID: 12368296 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fatty Acids
• RNA, Messenger
• Tumor Necrosis Factor-alpha
• Phytanic Acid
• Nitric Oxide

Topics

• Animals
• Apoptosis
• Blotting, Western
• Cells, Cultured
• Endothelium, Vascular (cytology, pathology)
• Enzyme Activation
• Fatty Acids (metabolism)
• Humans
• Mice
• Muscle, Smooth (cytology, pathology)
• Nitric Oxide (metabolism)
• Phytanic Acid (metabolism, pharmacology)
• Plasmids (metabolism)
• RNA, Messenger (metabolism)
• Rats
• Reverse Transcriptase Polymerase Chain Reaction
• Swine
• Time Factors
• Transfection
• Tumor Necrosis Factor-alpha (metabolism)
• Up-Regulation