Hemoglobin increases endothelin-1 in endothelial cells by decreasing nitric oxide.
We determined whether ferrous hemoglobin increases endothelin-1 (ET-1) secretion from bovine cerebral artery endothelial cells and the mechanisms involved. Exposure of endothelial cells to hemoglobin caused dose-dependent increases in pre-proET-1 mRNA and peptide. The increase in ET-1 peptide was inhibited by cycloheximide or actinomycin D whereas only cycloheximide decreased basal ET-1 release. N(G)-nitro-l-arginine significantly increased ET-1 concentration and reduced hemoglobin stimulation of ET-1 release. 8-Bromo-cGMP did not alter basal ET-1 concentration but suppressed hemoglobin-induced ET-1 production. Methemoglobin and S-nitrosylated methemoglobin were less potent inducers of ET-1 release. In summary, hemoglobin increases ET-1 in cerebral endothelial cells by mechanisms that involve transcription and translation. Nitric oxide production inhibits ET-1 production. Ferrous hemoglobin increases ET-1 by binding nitric oxide and abolishing this inhibitory pathway although other mechanisms are involved since N(G)-nitro-l-arginine reduces hemoglobin-induced ET-1 release.
Lin
G
G
Section of Neurosurgery, University of Chicago Medical Center, Pritzker School of Medicine, Chicago, Illinois 60637, USA.
Macdonald
R L
RL
Marton
L S
LS
Kowalczuk
A
A
Solenski
N J
NJ
Weir
B K
BK
D000818:Animals; D001483:Base Sequence; D002417:Cattle; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D017931:DNA Primers / Q000235:genetics; D003609:Dactinomycin / Q000494:pharmacology; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D016232:Endothelins / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism*; D006454:Hemoglobins / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019335:Nitroarginine / Q000494:pharmacology; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D017931:DNA Primers; D019332:Endothelin-1; D016232:Endothelins; D006454:Hemoglobins; D011498:Protein Precursors; D012333:RNA, Messenger; D003609:Dactinomycin; D019335:Nitroarginine; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D003513:Cycloheximide; D007770:L-Lactate Dehydrogenase; D006152:Cyclic GMP