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Biochemical and Molecular Actions of Nutrients

Zinc Modulates PPAR Signaling and Activation of Porcine Endothelial Cells¹

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

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

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

Dietary zinc has potent antioxidant and anti-inflammatory properties and is a critical component of peroxisome proliferator-activated receptor (PPAR) gene expression and regulation. To assess the protective mechanisms of PPAR in endothelial cell dysfunction and the role of zinc in the modulation of PPAR signaling, cultured porcine pulmonary artery endothelial cells were exposed to the membrane-permeable zinc chelator N,N,N'N'-tetrakis (2-pyridylmethyl)-ethylene diamine (TPEN), thiazolidinedione (TZD; PPAR agonist) or bisphenol A diglycidyl ether (BADGE; PPAR antagonist). Subsequently, endothelial cells were activated by treatment with linoleic acid (90 µmol/L) for 6 h. Zinc chelation by TPEN increased the DNA binding activity of nuclear factor (NF)-B and activator protein (AP)-1, decreased PPAR expression and activation as well as up-regulated interleukin (IL)-6 expression and production. These effects were fully reversed by zinc supplementation. In addition, exposure to TZD down-regulated linoleic acid-induced DNA binding activity of NF-B and AP-1, whereas BADGE further induced activation of these oxidative stress-sensitive transcription factors. Most importantly, the TZD-mediated down-regulation of NF-B and AP-1 and reduced inflammatory response were impaired during zinc chelation. These data suggest that zinc plays a critical role in PPAR signaling in linoleic acid-induced endothelial cell activation and indicate that PPAR signaling is impaired during zinc deficiency.

KEY WORDS: • zinc • PPAR • endothelial cells • linoleic acid • inflammation

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