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Nutrient-Gene Interactions

Peroxisome Proliferator Activated Receptors and Require Zinc for Their Anti-inflammatory Properties in Porcine Vascular Endothelial Cells¹

Gudrun Reiterer^*, Michal Toborek and Bernhard Hennig^**,2

^* Graduate Center for Nutritional Sciences Department of Surgery and ^** Molecular and Cell Nutrition Laboratory, College of Agriculture, University of Kentucky, Lexington, KY 40546-0215

²To whom correspondence should be addressed. E-mail: bhennig{at}uky.edu.

Zinc is an essential structural component of various proteins and is crucial for the integrity of the vascular endothelium. The present study focused on the effect of zinc deficiency on the anti-inflammatory properties of peroxisome proliferator activated receptor (PPAR) and agonists. Porcine pulmonary-arterial endothelial cells were deprived from zinc by chelator N,N,N',N'-tetrakis (2-pyridylmethyl)ethylene diamine. Cells were exposed to TNF- for 2 h following pretreament with the PPAR agonists fenofibrate or ciprofibrate or the PPAR agonists thiazolidinedione or troglitazone. The inflammatory response was tested by measuring nuclear factor-kappaB (NF-B) and activator protein-1 (AP-1) binding activities as well as by measuring mRNA expression levels of inflammatory genes, such as vascular cell adhesion molecule-1 (VCAM-1) and IL-6. All PPAR agonists tested lost their potency to downregulate the TNF-–induced inflammatory response in zinc-deficient cells. However, if zinc was added back, all PPAR agonists significantly downregulated the TNF-–mediated induction of inflammatory transcription factors NF-B and AP-1 and significantly reduced the expression of their target genes, VCAM-1 and IL-6. We therefore hypothesize that zinc is required for the PPAR and - DNA binding activity. Indeed, zinc deficiency significantly reduced the agonist-induced binding activity of PPAR and - to the PPAR response element. Our data demonstrate the importance of zinc in PPAR signaling and the requirement of zinc for the anti-inflammatory properties of PPAR and - agonists.

KEY WORDS: • atherosclerosis • vascular endothelial cells • PPAR • zinc • inflammation

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