Heme oxygenase-1 induction may explain the antioxidant profile of aspirin.
Aspirin is known to exert antioxidant effects by as yet unidentified mechanisms. In cultured endothelial cells derived from human umbilical vein, aspirin (30-300 microM) increased heme oxygenase-1 (HO-1) protein levels in a concentration-dependent fashion up to fivefold over basal levels. HO-1 induction was accompanied by a marked increase in catalytic activity of the enzyme as reflected by enhanced formation of both carbon monoxide and bilirubin. Pretreatment with aspirin or bilirubin at low micromolar concentrations protected endothelial cells from hydrogen peroxide-mediated toxicity. HO-1 induction and endothelial protection by aspirin were not mimicked by indomethacin, another inhibitor of cyclooxygenase. The nitric oxide (NO) synthase blocker L-NAME prevented aspirin-dependent HO-1 induction. These findings demonstrate that aspirin targets HO-1, presumably via NO-dependent pathways. Induction of HO-1 expression and activity may be a novel mechanism by which aspirin prevents cellular injury under inflammatory conditions and in cardiovascular disease.
Grosser
Nina
N
Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, Wolfgang-Langenbeck-Str. 4, Halle (Saale) 06099, Germany.
Abate
Aida
A
Oberle
Stefanie
S
Vreman
Hendrik J
HJ
Dennery
Phyllis A
PA
Becker
Jan C
JC
Pohle
Thorsten
T
Seidman
Daniel S
DS
Schröder
Henning
H
D000975:Antioxidants / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology*; D001663:Bilirubin / Q000737:chemistry / Q000378:metabolism; D002248:Carbon Monoxide / Q000737:chemistry / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007213:Indomethacin / Q000378:metabolism; D007249:Inflammation; D008565:Membrane Proteins; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D016877:Oxidants / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology
D000975:Antioxidants; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D016877:Oxidants; D002248:Carbon Monoxide; D006861:Hydrogen Peroxide; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D001241:Aspirin; D001663:Bilirubin; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin