© 2000 American Heart Association, Inc.
Vascular Biology |
Heme Oxygenase-1 Is a cGMP-Inducible Endothelial Protein and Mediates the Cytoprotective Action of Nitric Oxide
From the Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, Halle, Germany, and the Department of Pediatrics (P.A.D.), Stanford University School of Medicine, Stanford, Calif.
Correspondence to Dr Henning Schröder, School of Pharmacy, Martin Luther University, Wolfgang-Langenbeck-Str. 4, 06099 Halle (Saale), Germany. E-mail schroeder{at}pharmazie.uni-halle.de
Abstract—Inducible heme
oxygenase (HO-1) has recently been recognized as an
antioxidant and cytoprotective gene. By use of Western blotting, cell
viability analysis, and antisense technique, the present
study investigates the involvement of HO-1 in
endothelial protection induced by the clinically used
nitric oxide (NO) donor molsidomine (specifically, its active
metabolite 3-morpholinosydnonimine [SIN-1]) and the second messenger
cGMP. In bovine pulmonary artery endothelial
cells, SIN-1 and
S-nitroso-N-acetyl-D,L-penicillamine
(SNAP) at 1 to 100 µmol/L induced the synthesis of HO-1 protein
in a concentration-dependent fashion up to 3-fold over basal levels.
HO-1 induction by SIN-1 was inhibited in the presence of the NO
scavenger phenyl-4,4,5,5,-tetramethylimidazoline-1-oxyl-3-oxide and the
soluble guanylyl cyclase inhibitor
1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one.
8-Bromo-cGMP (1 to 100 µmol/L) and dibutyryl cGMP (1 to 100
µmol/L) as well as the activator of particulate guanylyl
cyclase atrial natriuretic peptide (1 to 100 nmol/L)
produced increases in HO-1 protein similar to those produced by SIN-1.
SIN-1 and 8-bromo-cGMP increased heme oxygenase
activity (bilirubin formation). Cytoprotection by NO donors was
abrogated in the presence of the heme oxygenase
inhibitor tin protoporphyrin IX. Pretreatment of cells with
a phosphorothioate-linked HO-1 antisense
oligonucleotide prevented protection by SIN-1 or
8-bromo-cGMP against tumor necrosis factor-
cytotoxicity, whereas
sense and scrambled HO-1 were without effect under these conditions.
Our results show for the first time that HO-1 is a cGMP-sensitive
endothelial gene and establish conclusively a causal
relationship between HO-1 induction and endothelial
protection by the NO/cGMP system. By targeting cytoprotective HO-1, NO
donors may therefore be expected to induce antioxidant,
antiatherogenic, and anti-inflammatory effects.
Key Words: cGMP • cytoprotection • endothelial cells • heme oxygenase-1 • nitric oxide
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