Human sickle cell blood modulates endothelial heme oxygenase activity: effects on vascular adhesion and reactivity.
OBJECTIVE
Sickle cell disease (SCD) is characterized by extensive hemolysis, increased cellular adhesion, and vaso-occlusion. Tissues from sickle patients express heme oxygenase-1 (HO-1), the enzyme that degrades free heme/hemoglobin to the signaling molecule carbon monoxide, and the antioxidants biliverdin/bilirubin. Here, we examined the HO response in endothelial cells exposed to human sickle blood and determined whether this response is beneficial for SCD.


RESULTS
We measured HO activity in human and bovine aortic endothelial cells incubated with human sickle or normal blood. Sickle blood increased HO activity, which was enhanced by hypoxia and was caused mainly by the red cell components of sickle blood. Oxidized hemoglobin was higher in sickle blood and increased markedly over time. Interestingly, HO activity correlated inversely with patients' hemoglobin levels and positively with bilirubin and lactate dehydrogenase. HO-1 induction, exogenous biliverdin, or carbon monoxide markedly decreased adhesion of sickle blood to the endothelium, and sickle red cells partially inhibited relaxation mediated by carbon monoxide in isolated aortas.


CONCLUSIONS
Our results highlight important associations between SCD and HO byproducts, which may counteract vascular complications of SCD.
Bains
Sandip K
SK
Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex, United Kingdom.
Foresti
Roberta
R
Howard
Jo
J
Atwal
Sangeeta
S
Green
Colin J
CJ
Motterlini
Roberto
R
D000328:Adult; D000755:Anemia, Sickle Cell / Q000097:blood* / Q000201:enzymology / Q000503:physiopathology / Q000628:therapy; D000818:Animals; D001663:Bilirubin / Q000097:blood; D001664:Biliverdine / Q000378:metabolism; D001880:Boranes / Q000378:metabolism / Q000494:pharmacology; D002245:Carbon Dioxide / Q000378:metabolism; D002254:Carbonates / Q000378:metabolism / Q000494:pharmacology; D016022:Case-Control Studies; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D004912:Erythrocytes / Q000378:metabolism*; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism; D006461:Hemolysis; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D008875:Middle Aged; D009942:Organometallic Compounds / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D012189:Retrospective Studies; D013997:Time Factors; D014664:Vasodilation; D055815:Young Adult
D001880:Boranes; D002254:Carbonates; D006454:Hemoglobins; D009942:Organometallic Compounds; C503854:sodium boranocarbonate; C476530:tricarbonylchloro(glycinato)ruthenium(II); D002245:Carbon Dioxide; D007770:L-Lactate Dehydrogenase; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D001664:Biliverdine; D001663:Bilirubin