Heme oxygenase-1 induction may explain the antioxidant profile of pentaerythrityl trinitrate.
The organic nitrate pentaerythrityl tetranitrate (PETN) is known to exert long-term antioxidant and antiatherogenic effects by as yet unidentified mechanisms. In cultured endothelial cells derived from human umbilical vein, the active PETN metabolite PETriN (0.01-1 mM) increased heme oxygenase (HO)-1 mRNA and protein levels in a concentration-dependent fashion. HO-1 induction was accompanied by a marked increase in catalytic activity of the enzyme as reflected by enhanced formation of carbon monoxide and bilirubin. Pretreatment with PETriN or bilirubin at low micromolar concentrations protected endothelial cells from hydrogen peroxide-mediated toxicity. HO-1 induction and endothelial protection by PETriN were not mimicked by isosorbide dinitrate, another long-acting nitrate. The present study demonstrates that PETriN stimulates mRNA and protein expression as well as enzymatic activity of the antioxidant defense protein HO-1 in endothelial cells. Increased HO-1 expression and ensuing formation of cytoprotective bilirubin may contribute to and explain the specific antioxidant and antiatherogenic actions of PETN.
Oberle
Stefanie
S
Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Strasse 4, Halle (Saale) 06099, Germany.
Abate
Aida
A
Grosser
Nina
N
Vreman
Hendrik J
HJ
Dennery
Phyllis A
PA
Schneider
Heinz T
HT
Stalleicken
Dirk
D
Schröder
Henning
H
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001663:Bilirubin / Q000096:biosynthesis / Q000502:physiology; D002384:Catalysis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis* / Q000235:genetics; D051547:Heme Oxygenase-1; D006801:Humans; D008565:Membrane Proteins; D010417:Pentaerythritol Tetranitrate / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D013552:Swine
D000975:Antioxidants; D008565:Membrane Proteins; D012333:RNA, Messenger; D010417:Pentaerythritol Tetranitrate; C100210:pentrinitrol; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D001663:Bilirubin