Zinc modulates PPARgamma signaling and activation of porcine endothelial cells.
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 PPARgamma in endothelial cell dysfunction and the role of zinc in the modulation of PPARgamma 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; PPARgamma agonist) or bisphenol A diglycidyl ether (BADGE; PPARgamma antagonist). Subsequently, endothelial cells were activated by treatment with linoleic acid (90 micro mol/L) for 6 h. Zinc chelation by TPEN increased the DNA binding activity of nuclear factor (NF)-kappaB and activator protein (AP)-1, decreased PPARgamma 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-kappaB and AP-1, whereas BADGE further induced activation of these oxidative stress-sensitive transcription factors. Most importantly, the TZD-mediated down-regulation of NF-kappaB and AP-1 and reduced inflammatory response were impaired during zinc chelation. These data suggest that zinc plays a critical role in PPARgamma signaling in linoleic acid-induced endothelial cell activation and indicate that PPARgamma signaling is impaired during zinc deficiency.
Meerarani
Purushothaman
P
Molecular and Cell Nutrition Laboratory, College of Agriculture, University of Kentucky, Lexington, KY 40546-0215, USA.
Reiterer
Gudrun
G
Toborek
Michal
M
Hennig
Bernhard
B
D000818:Animals; D001559:Benzhydryl Compounds; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004032:Diet; D024202:Electrophoretic Mobility Shift Assay; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology*; D004852:Epoxy Compounds; D005029:Ethylenediamines / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D019787:Linoleic Acid / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D011651:Pulmonary Artery; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013552:Swine; D045162:Thiazolidinediones / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015032:Zinc / Q000494:pharmacology*; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D002614:Chelating Agents; D004247:DNA; D004852:Epoxy Compounds; D005029:Ethylenediamines; D015850:Interleukin-6; D019787:Linoleic Acid; D016328:NF-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D015032:Zinc; C089946:2,4-thiazolidinedione; C019273:bisphenol A diglycidyl ether; D000098826:Bisphenol A Compounds; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine