title: Zinc regulates iNOS-derived nitric oxide formation in endothelial cells.
abstract: Aberrant production of nitric oxide (NO) by inducible NO synthase (iNOS) has been implicated in the pathogenesis of endothelial dysfunction and vascular disease. Mechanisms responsible for the fine-tuning of iNOS activity in inflammation are still not fully understood. Zinc is an important structural element of NOS enzymes and is known to inhibit its catalytical activity. In this study we aimed to investigate the effects of zinc on iNOS activity and expression in endothelial cells. We found that zinc down-regulated the expression of iNOS (mRNA+protein) and decreased cytokine-mediated activation of the iNOS promoter. Zinc-mediated regulation of iNOS expression was due to inhibition of NF-κB transactivation activity, as determined by a decrease in both NF-κB-driven luciferase reporter activity and expression of NF-κB target genes, including cyclooxygenase 2 and IL-1β. However, zinc did not affect NF-κB translocation into the nucleus, as assessed by Western blot analysis of nuclear and cytoplasmic fractions. Taken together our results demonstrate that zinc limits iNOS-derived high output NO production in endothelial cells by inhibiting NF-κB-dependent iNOS expression, pointing to a role of zinc as a regulator of iNOS activity in inflammation.
authors.affiliation: Cardiovascular Research Laboratory, Department of Cardiology, Pneumology, and Angiology, Medical Faculty, Heinrich-Heine-University of Düsseldorf, Universitätsstr. 1, Düsseldorf D-40225, Germany ; Research Group Immunobiology, Medical Faculty, Heinrich-Heine-University of Düsseldorf, Universitätsstr. 1, Düsseldorf D-40225, Germany.
authors.forename: Miriam M
authors.initials: MM
authors.lastname: Cortese-Krott
authors.affiliation: Cardiovascular Research Laboratory, Department of Cardiology, Pneumology, and Angiology, Medical Faculty, Heinrich-Heine-University of Düsseldorf, Universitätsstr. 1, Düsseldorf D-40225, Germany ; Department of Trauma and Hand Surgery, Medical Faculty, Heinrich-Heine-University of Düsseldorf, Universitätsstr. 1, Düsseldorf D-40225, Germany.
authors.forename: Larissa
authors.initials: L
authors.lastname: Kulakov
authors.affiliation: Department of Trauma and Hand Surgery, Medical Faculty, Heinrich-Heine-University of Düsseldorf, Universitätsstr. 1, Düsseldorf D-40225, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Opländer
authors.affiliation: Research Group Immunobiology, Medical Faculty, Heinrich-Heine-University of Düsseldorf, Universitätsstr. 1, Düsseldorf D-40225, Germany.
authors.forename: Victoria
authors.initials: V
authors.lastname: Kolb-Bachofen
authors.affiliation: Institute of Biochemistry and Molecular Biology I, Medical Faculty, Heinrich-Heine-University of Düsseldorf, Universitätsstr. 1, Düsseldorf D-40225, Germany.
authors.forename: Klaus-D
authors.initials: KD
authors.lastname: Kröncke
authors.affiliation: Research Group Immunobiology, Medical Faculty, Heinrich-Heine-University of Düsseldorf, Universitätsstr. 1, Düsseldorf D-40225, Germany ; Department of Trauma and Hand Surgery, Medical Faculty, Heinrich-Heine-University of Düsseldorf, Universitätsstr. 1, Düsseldorf D-40225, Germany.
authors.forename: Christoph V
authors.initials: CV
authors.lastname: Suschek
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D051381:Rats; D015032:Zinc / Q000494:pharmacology*
chemical_list: D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D015032:Zinc
keywords: Endothelial cells; Gene expression; Inducible nitric oxide synthase; NF-κB; Zinc