The antioxidant defense protein ferritin is a novel and specific target for pentaerithrityl tetranitrate in endothelial cells.
The organic nitrate pentaerithrityl tetranitrate (PETN) is known to exert long-term antioxidant and antiatherogenic effects by as yet unidentified mechanisms. In porcine aortic endothelial cells, a 24 h incubation with PETN (1-100 microM) or its metabolite pentaerithrityl trinitrate (PETriN) increased levels of the antioxidant protein ferritin up to three-fold over basal, whereas isosorbide dinitrate and isosorbide-5-mononitrate were without significant effect under these conditions. PETriN-induced ferritin expression was blocked by the NO scavenger PTIO but remained unaltered in the presence of ODQ, an inhibitor of soluble guanylyl cyclase. 8-Bromo cyclic GMP and dibutyryl cyclic GMP did not influence basal ferritin synthesis. The iron chelator desferrioxamine abolished ferritin induction by PETriN. Our results show that PETN or its active metabolite PETriN induce ferritin synthesis through NO- and iron-dependent but cyclic GMP-independent pathways. Increased activity of ferritin may contribute to, and at least in part explain, the specific antiatherogenic and antioxidant action of PETN.
Oberle
S
S
School of Pharmacy, Martin Luther University, Wolfgang-Langenbeck-Strasse 4, Halle (Saale), 06099, Germany.
Schwartz
P
P
Abate
A
A
Schröder
H
H
D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology; D001011:Aorta; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005293:Ferritins / Q000096:biosynthesis*; D016166:Free Radical Scavengers / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D007502:Iron Chelating Agents / Q000494:pharmacology; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009589:Nitrogen Oxides; D010417:Pentaerythritol Tetranitrate / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D013552:Swine
D000975:Antioxidants; D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D007093:Imidazoles; D007502:Iron Chelating Agents; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D010417:Pentaerythritol Tetranitrate; C091861:spermine nitric oxide complex; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; D013096:Spermine; D009569:Nitric Oxide; C100210:pentrinitrol; D005293:Ferritins; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D007548:Isosorbide Dinitrate; D003676:Deferoxamine